Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Clinical Pharmacokinetics
Published in: Clinical Pharmacokinetics 12/2002

01-10-2002 | Review Article

Clinical Significance of the Cytochrome P450 2C19 Genetic Polymorphism

Authors: Zeruesenay Desta, Xiaojiong Zhao, Jae-Gook Shin, Dr David A. Flockhart

Published in: Clinical Pharmacokinetics | Issue 12/2002

Login to get access

Abstract

Cytochrome P450 2C19 (CYP2C19) is the main (or partial) cause for large differences in the pharmacokinetics of a number of clinically important drugs. On the basis of their ability to metabolise (S)-mephenytoin or other CYP2C19 substrates, individuals can be classified as extensive metabolisers (EMs) or poor metabolisers (PMs). Eight variant alleles (CYP2C19*2 to CYP2C19*8) that pre-diet PMs have been identified. The distribution of EM and PM genotypes and phenotypes shows wide interethnic differences. Nongenetic factors such as enzyme inhibition and induction, old age and liver cirrhosis can also modulate CYP2C19 activity.
In EMs, ∼80% of doses of the proton pump inhibitors (PPIs) omeprazole, lansoprazole and pantoprazole seem to be cleared by CYP2C19, whereas CYP3A is more important in PMs. Five-fold higher exposure to these drugs is observed in PMs than in EMs of CYP2C19, and further increases occur during inhibition of CYP3A-catalysed alternative metabolic pathways in PMs. As a result, PMs of CYP2C19 experience more effective acid suppression and better healing of duodenal and gastric ulcers during treatment with omeprazole and lansoprazole compared with EMs. The pharmacoeconomic value of CYP2C19 genotyping remains unclear. Our calculations suggest that genotyping for CYP2C19 could save approximately $US5000 for every 100 Asians tested, but none for Caucasian patients. Nevertheless, genotyping for the common alleles of CYP2C19 before initiating PPIs for the treatment of reflux disease and H. pylori infection is a cost effective tool to determine appropriate duration of treatment and dosage regimens. Altered CYP2C19 activity does not seem to increase the risk for adverse drug reactions/interactions of PPIs.
Phenytoin plasma concentrations and toxicity have been shown to increase in patients taking inhibitors of CYP2C19 or who have variant alleles and, because of its narrow therapeutic range, genotyping of CYP2C19 in addition to CYP2C9 may be needed to optimise the dosage of phenytoin. Increased risk of toxicity of tricyclic antidepressants is likely in patients whose CYP2C19 and/or CYP2D6 activities are diminished. CYP2C19 is a major enzyme in proguanil activation to cycloguanil, but there are no clinical data that suggest that PMs of CYP2C19 are at a greater risk for failure of malaria prophylaxis or treatment. Diazepam clearance is clearly diminished in PMs or when inhibitors of CYP2C19 are coprescribed, but the clinical consequences are generally minimal.
Finally, many studies have attempted to identify relationships between CYP2C19 genotype and phenotype and susceptibility to xenobiotic-induced disease, but none of these are compelling.
Literature
1.
Kupfer A, Desmond PV, Schenker S, et al. Family study of a genetically determined deficiency of mephenytoin hydroxyl-ation in man [letter]. Pharmacologist 1979; 21: 173
2.
de Morais SM, Wilkinson GR, Blaisdell J, et al. The major genetic defect responsible for the polymorphism of S-mephenytoin metabolism in humans. J Biol Chem 1994; 269: 15419–22PubMed
3.
Goldstein JA, de Morais SM. Biochemistry and molecular biology of the human CYP2C subfamily. Pharmacogenetics 1994; 4: 285–99PubMedCrossRef
4.
Wrighton SA, Stevens JC, Becker GW, et al. Isolation and characterization of human liver cytochrome P450 2C19: correlation between 2C19 and S-mephenytoin 4′-hydroxylation. Arch Biochem Biophys 1993; 306: 240–5PubMedCrossRef
5.
Goldstein JA, Faletto MB, Romkes-Sparks M, et al. Evidence that CYP2C19 is the major (S)-mephenytoin 4-hydroxylase in humans. Biochemistry 1994; 33: 1743–52PubMedCrossRef
6.
Kupfer A, Bircher J. Stereoselectivity of differential routes of drug metabolism: the fate of the enantiomers of [14C]-mephenytoin in the dog. J Pharmacol Exp Ther 1979; 209: 190–5PubMed
7.
Kupfer A, Roberts RK, Schenker S, et al. Stereoselective metabolism of mephenytoin in man. J Pharmacol Exp Ther 1981; 218: 193–9PubMed
8.
Kupfer A, Desmond PV, Patwardhan R, et al. Mephenytoin hydroxylation deficiency: kinetics after repeated doses. Clin Pharmacol Ther 1984; 35: 33–9PubMedCrossRef
9.
Kupfer A, Preisig R. Pharmacogenetics of mephenytoin: a new drug hydroxylation polymorphism in man. Eur J Clin Pharmacol 1984; 26: 753–9PubMedCrossRef
10.
Kupfer A, Desmond PV, Schenker S, et al. Stereoselective metabolism and disposition of the enantiomers of mephenytoin during chronic oral administration of the racemic drug in man. J Pharmacol Exp Ther 1982; 221: 590–7PubMed
11.
Inaba T, Jurima M, Kalow W. Family studies of mephenytoin hydroxylation deficiency. Am J Hum Genet 1986; 38: 768–72PubMed
12.
Wilkinson GR, Guengerich FP, Branch RA. Genetic polymorphism of S-mephenytoin hydroxylation. Pharmacol Ther 1989; 43: 53–76PubMedCrossRef
13.
Daniel HI, Edeki TI. Genetic polymorphism of S-mephenytoin 4′-hydroxylation. Psychopharmacol Bull 1996; 32: 219–30PubMed
14.
Xie HG, Kim RB, Stein CM, et al. Genetic polymorphism of (S)-mephenytoin 4′-hydroxylation in populations of African descent. Br J Clin Pharmacol 1999; 48: 402–8PubMedCrossRef
15.
Xie HG, Stein CM, Kim RB, et al. Allelic, genotypic and phe-notypic distributions of S-mephenytoin 4′-hydroxylase (CYP-2C19) in healthy Caucasian populations of European descent throughout the world. Pharmacogenetics 1999; 9: 539–49PubMedCrossRef
16.
17.
Bertilsson L. Geographical/interracial differences in polymorphic drug oxidation. Clin Pharmacokinet 1995; 29: 192–209PubMedCrossRef
18.
Meyer UA, Zanger UM. Molecular mechanisms of genetic polymorphisms of drug metabolism. Annu Rev Pharmacol Toxicol 1997; 37: 269–96PubMedCrossRef
19.
20.
Romkes M, Faletto MB, Blaisdell J, et al. Cloning and expression of complementary DNAs for multiple members of the human cytochrome P450IIC subfamily. Biochemistry 1991; 30: 3247–55PubMedCrossRef
21.
Zaphiropoulos PG. RNA molecules containing exons originating from different members of the cytochrome P450 2C gene subfamily (CYP2C) in human epidermis and liver. Nucleic Acids Res 1999; 27: 2585–90PubMedCrossRef
22.
Obach RS, Zhang QY, Dunbar D, et al. Metabolic characterization of the major human small intestinal cytochrome p450s. Drug Metab Dispos 2001; 29: 347–52PubMed
23.
de Morais SM, Wilkinson GR, Blaisdell J, et al. Identification of a new genetic defect responsible for the polymorphism of (S)-mephenytoin metabolism in Japanese. Mol Pharmacol 1994; 46: 594–8PubMed
24.
Xie HG, Kim RB, Wood AJ, et al. Molecular basis of ethnic differences in drug disposition and response. Annu Rev Pharmacol Toxicol 2001; 41: 815–50PubMedCrossRef
25.
Goldstein JA, Ishizaki T, Chiba K, et al. Frequencies of the defective CYP2C19 alleles responsible for the mephenytoin poor olizer phenotype in various Oriental, Caucasian, Saudi Arabian and American Black populations. Pharmacogenetics 1997; 7: 59–64PubMedCrossRef
26.
Richardson TH, Jung F, Griffin KJ, et al. A universal approach to the expression of human and rabbit cytochrome P450s of the 2C subfamily in Escherichia coli. Arch Biochem Biophys 1995; 323: 87–96PubMedCrossRef
27.
Ibeanu GC, Goldstein JA, Meyer UA, et al. Identification of new human CYP2C19 alleles (CYP2C19*6 and CYP2C-19*2B) in a Caucasian poor metabolizer of mephenytoin. J Pharmacol Exp Ther 1998; 286: 1490–5PubMed
28.
de Morais SMF, Goldstein JA, Xie HG, et al. Genetic analysis of the S-mephenytoin polymorphism in a Chinese population. Clin Pharmacol Ther 1995; 58: 404–12PubMedCrossRef
29.
Ferguson RJ, de Morais SM, Benhamou S, et al. A new genetic defect in human CYP2C19: mutation of the initiation codon is responsible for poor metabolism of S-mephenytoin. J Pharmacol Exp Ther 1998; 284: 356–61PubMed
30.
Ibeanu GC, Blaisdell J, Ghanayem BI, et al. An additional defective allele, CYP2C19*5, contributes to the S-mephenytoin poor metabolizer phenotype in Caucasians. Pharmacogenet-ics 1998; 8: 129–35CrossRef
31.
Xiao ZS, Goldstein JA, Xie HG, et al. Differences in the incidence of the CYP2C19 polymorphism affecting the S-mephenytoin phenotype in Chinese Han and Bai populations and identification of a new rare CYP2C19 mutant allele. J Pharmacol Exp Ther 1997; 281: 604–9PubMed
32.
Ibeanu GC, Blaisdell J, Ferguson RJ, et al. A novel transversion in the intron 5 donor splice junction of CYP2C19 and a sequence polymorphism in exon 3 contribute to the poor metabolizer phenotype for the anticonvulsant drug S-mephenytoin. J Pharmacol Exp Ther 1999; 290: 635–40PubMed
33.
Aklillu E, Persson I, Bertilsson L, et al. Frequent distribution of ultrarapid metabolizers of debrisoquine in an Ethiopian population carrying duplicated and multiduplicated functional CYP2D6 alleles. J Pharmacol Exp Ther 1996; 278: 441–6PubMed
34.
Balian JD, Sukhova N, Harris JW, et al. The hydroxylation of omeprazole correlates with S-mephenytoin metabolism: a population study. Clin Pharmacol Ther 1995; 57: 662–9PubMedCrossRef
35.
Nakamura K, Goto F, Ray WA, et al. Interethnic differences in genetic polymorphism of debrisoquin and mephenytoin hydroxylation between Japanese and Caucasian populations. Clin Pharmacol Ther 1985; 38: 402–8PubMedCrossRef
36.
Jurima M, Inaba T, Kadar D, et al. Genetic polymorphism of mephenytoin p(4′)-hydroxylation: difference between Orientals and Caucasians. Br J Clin Pharmacol 1985; 19: 483–7PubMedCrossRef
37.
Bertilsson L, Lou YQ, Du YL, et al. Pronounced differences between native Chinese and Swedish populations in the polymorphic hydroxylations of debrisoquin and S-mephenytoin. Clin Pharmacol Ther 1992; 51: 388–97PubMedCrossRef
38.
Sohn DR, Kusaka M, Ishizaki T, et al. Incidence of S-mephenytoin hydroxylation deficiency in a Korean population and the interphenotypic differences in diazepam pharmacokinetics. Clin Pharmacol Ther 1992; 52: 160–9PubMedCrossRef
39.
Edeki TI, Goldstein JA, de Morais SM, et al. Genetic polymorphism of S-mephenytoin 4′-hydroxylation in African-Americans. Pharmacogenetics 1996; 6: 357–60PubMedCrossRef
40.
Inaba T, Jorge LF, Arias TD. Mephenytoin hydroxylation in the Cuna Amerindians of Panama. Br J Clin Pharmacol 1988; 25: 75–9PubMedCrossRef
41.
Kaneko A, Laneko O, Taleo G, et al. High frequencies of CYP2C19 mutations and poor metabolism of proguanil in Vanuatu. Lancet 1997; 349: 921–2PubMedCrossRef
42.
Kubota T, Chiba K, Ishizaki T. Genotyping of S-mephenytoin 4′-hydroxylation in an extended Japanese population. Clin Pharmacol Ther 1996; 60: 661–6PubMedCrossRef
43.
Horai Y, Nakano M, Ishizaki T, et al. Metoprolol and mephenytoin oxidation polymorphisms in Far Eastern Oriental subjects: Japanese versus Mainland Chinese. Clin Pharmacol Ther 1989; 46: 198–207PubMedCrossRef
44.
Relling MV. Polymorphic drug metabolism. Clin Pharm 1989; 8: 852–63PubMed
45.
Roh HK, Dahl ML, Tybring G, et al. Cyp2cl9 genotype and phenotype determined by omeprazole in a Korean population. Pharmacogenetics 1996; 6: 547–51PubMedCrossRef
46.
Weerasuriya K, Jayakody RL, Smith CA, et al. Debrisoquine and mephenytoin oxidation in Sinhalese: a population study. Br J Clin Pharmacol 1994; 34: 466–70CrossRef
47.
Lamba JK, Dhiman RK, Kohli KK. Genetic polymorphism of the hepatic cytochrome P4502C19 in north Indian subjects. Clin Pharmacol Ther 1998; 63: 422–7PubMedCrossRef
48.
Doshi BS, Kulkarni RD, Chauhan BL, et al. Frequency of impaired mephenytoin 4′-hydroxylation in an Indian population [letter]. Br J Clin Pharmacol 1990; 30: 779–80PubMedCrossRef
49.
Setiabudy R, Kusaka M, Chiba K, et al. Dapsone N-acetylation, metoprolol alpha-hydroxylation, and S-mephenytoin 4-hy-droxylation polymorphisms in an Indonesian population: a cocktail and extended phenotyping assessment trial. Clin Pharmacol Ther 1994; 56: 142–53PubMedCrossRef
50.
Brosen K, Skjelbo E, Flachs H. Proguanil metabolism is determined by the mephenytoin oxidation polymorphism in Vietnamese living in Denmark. Br J Clin Pharmacol 1993; 36: 105–8PubMedCrossRef
51.
Wanwimolruk S, Bhawan S, Coville PF, et al. Genetic polymorphism of debrisoquine (CYP2D6) and proguanil (CYP2C19) in South Pacific Polynesian population. Eur J Clin Pharmacol 1998; 54: 431–5PubMedCrossRef
52.
Clasen K, Madsen L, Brosen K, et al. Sparteine and mephenytoin oxidation: genetic polymorphisms in east and west Greenland. Clin Pharmacol Ther 1991; 49: 624–31PubMedCrossRef
53.
Basci NE, Brosen K, Bozkurt A, et al. S-Mephenytoin, sparteine and debrisoquine oxidation: genetic polymorphisms in a Turkish population. Br J Clin Pharmacol 1994; 38: 463–5PubMedCrossRef
54.
Hadidi HF, Irshaid YM, Woosley RL, et al. S-Mephenytoin hydroxylation phenotypes in a Jordanian population. Clin Pharmacol Ther 1995; 58: 542–7PubMedCrossRef
55.
Sviri S, Shpizen S, Leitersdorf E, et al. Phenotypic-genotypic analysis of CYP2C19 in the Jewish Israeli population. Clin Pharmacol Ther 1999; 65: 275–82PubMedCrossRef
56.
Herrlin K, Massele AY, Jande M, et al. Bantu Tanzanians have a decreased capacity to metabolize omeprazole and mephenytoin in relation to their CYP2C19 genotype. Clin Pharmacol Ther 1998; 64: 391–401PubMedCrossRef
57.
Skjelbo E, Mutabingwa TK, Bygbjerg LB, et al. Chloroguanide metabolism in relation to the efficacy in malaria prophylaxis and the S-mephenytoin oxidation in Tanzanians. Clin Pharmacol Ther 1996; 59: 304–11PubMedCrossRef
58.
Masimirembwa C, Bertilsson L, Johansson I, et al. Phenotyping and genotyping of S-mephenytoin hydroxylase (cytochrome P450 2C19) in a Shona population of Zimbabwe. Clin Pharmacol Ther 1995; 57: 656–61PubMedCrossRef
59.
Persson I, Aklillu E, Rodrigues F, et al. S-Mephenytoin hydroxylation phenotype and cyp2cl9 genotype among Ethiopians. Pharmacogenetics 1996; 6: 521–6PubMedCrossRef
60.
Yamada H, Dahl ML, Lannfelt L, et al. CYP2D6 and CYP2C19 genotypes in an elderly Swedish population. Eur J Clin Pharmacol 1998; 54: 479–81PubMedCrossRef
61.
Sanz EJ, Villen T, Aim C, et al. S-Mephenytoin hydroxylation phenotypes in a Swedish population determined after coadministration with debrisoquin. Clin Pharmacol Ther 1989; 45: 495–9PubMedCrossRef
62.
Jacqz E, Dulac H, Mathieu H. Phenotyping polymorphic drug metabolism in the French Caucasian population. Eur J Clin Pharmacol 1988; 35: 167–71PubMedCrossRef
63.
Drohse A, Bathum L, Brosen K, et al. Mephenytoin and sparteine oxidation: genetic polymorphisms in Denmark. Br J Clin Pharmacol 1989; 27: 620–5PubMedCrossRef
64.
Bathum L, Andersen-Ranberg K, Boldsen J, et al. Genotypes for the cytochrome P450 enzymes CYP2D6 and CYP2C19 in human longevity: role of CYP2D6 and CYP2C19 in longevity. Eur J Clin Pharmacol 1998; 54: 427–30PubMedCrossRef
65.
Ruas JL, Lechner MC. Allele frequency of cyp2c 19 in a Portuguese population. Pharmacogenetics 1997; 7: 333–5PubMedCrossRef
66.
Reviriego J, Bertilsson L, Carrillo JA, et al. Frequency of S-mephenytoin hydroxylation deficiency in 373 Spanish subjects compared to other Caucasian populations. Eur J Clin Pharmacol 1993; 44: 593–5PubMedCrossRef
67.
Marandi T, Dahl ML, Rago L, et al. Debrisoquine and S-mephenytoin hydroxylation polymorphisms in a Russian population living in Estonia. Eur J Clin Pharmacol 1997; 53: 257–60PubMedCrossRef
68.
Marandi T, Dahl ML, Kiivet RA, et al. Debrisoquin and S-mephenytoin hydroxylation phenotypes and CYP2D6 genotypes in an Estonian population. Pharmacol Toxicol 1996; 78: 303–7PubMedCrossRef
69.
Hoskins JM, Shenfield GM, Gross AS. Relationship between proguanil metabolic ratio and CYP2C19 genotype in a Caucasian population. Br J Clin Pharmacol 1998; 46: 499–504PubMedCrossRef
70.
Marinac J, Balian JD, Foxworth JW, et al. Determination of CYP2C19 phenotype in black Americans: correlation with genotype. Clin Pharmacol Ther 1996; 60: 138–44PubMedCrossRef
71.
Martin DE, Flockhart DA, Jorkasky DK. Analysis of CYP2D6 and CYP2C19 genotypes in large African-American (AA) and Caucasian (C) population [abstract]. Clin Pharmacol Ther 1998; 63: 206
72.
Wedlund PJ, Aslanian WS, McAllister CB, et al. Mephenytoin hydroxylation deficiency in Caucasians: frequency of a new oxidative drug metabolism polymorphism. Clin Pharmacol Ther 1984; 36: 773–80PubMedCrossRef
73.
Inaba T, Jurima M, Nakano M, et al. Mephenytoin and sparteine pharmacogenetics in Canadian Caucasians. Clin Pharmacol Ther 1984; 36: 670–6PubMedCrossRef
74.
Nowak MP, Sellers EM, Tyndale RF. Canadian Native Indians exhibit unique CYP2A6 and CYP2C19 mutant allele frequencies. Clin Pharmacol Ther 1998; 64: 378–83PubMedCrossRef
75.
Jurima-Romet M, Goldstein JA, Le Belle M, et al. CYP2C19 genotyping and associated mephenytoin hydroxylation polymorphism in a Canadian Inuit population. Pharmacogenetics 1996; 6: 329–39PubMedCrossRef
76.
Griese EU, Ilett KF, Kitteringham NR, et al. Allele and genotype frequencies of polymorphic cytochromes P4502D6, 2C19 and 2E1 in aborigines from western Australia. Pharmacogenetics 2001; 11: 69–76PubMedCrossRef
77.
Zhang YA, Reviriego J, Lou YQ, et al. Diazepam metabolism in native Chinese poor and extensive hydroxylators of S-mephenytoin: interethnic differences in comparison with white subjects. Clin Pharmacol Ther 1990; 48: 496–502PubMedCrossRef
78.
Ishizaki T, Sohn DR, Kobayashi K, et al. Interethnic differences in omeprazole metabolism in the two S-mephenytoin hydroxylation phenotypes studied in Caucasians and Orientals. Ther Drug Monit 1994; 16: 214–5PubMedCrossRef
79.
Shintani M, Ieiri I, Inoue K, et al. Genetic polymorphisms and functional characterization of the 5′-flanking region of the human CYP2C9 gene: in vitro and in vivo studies. Clin Pharmacol Ther 2001; 70: 175–82PubMedCrossRef
80.
Herrin K. CYP2C19 catalyzed drug metabolism in different populations [dissertation]. Stockholm: Karolinska Institute, 2001 Jun 6
81.
Bathum L, Skjelbo E, Mutabingwa TK, et al. Phenotypes and genotypes for CYP2D6 and CYP2C19 in a black Tanzanian population. Br J Clin Pharmacol 1999; 48: 395–401PubMedCrossRef
82.
Somogyi AA, Reinhard HA, Bochner F. Effects of omeprazole and cimetidine on the urinary metabolic ratio of proguanil in healthy volunteers. Eur J Clin Pharmacol 1996; 50: 417–9PubMedCrossRef
83.
Andersson T, Andren K, Cederberg C, et al. Effect of omeprazole and cimetidine on plasma diazepam levels. Eur J Clin Pharmacol 1990; 39: 51–4PubMedCrossRef
84.
Glue P, Banfield CR, Perhach JL, et al. Pharmacokinetic interactions with felbamate: in vitro-in vivo correlation. Clin Phar-macokinet 1997; 33: 214–24CrossRef
85.
Jeppesen U, Gram LF, Vistisen K, et al. Dose-dependent inhibition of CYP1A2, CYP2C19 and CYP2D6 by citalopram, fluoxetine, fluvoxamine and paroxetine. Eur J Clin Pharmacol 1996; 51: 73–8PubMedCrossRef
86.
Kobayashi K, Yamamoto T, Chiba K, et al. The effects of selective serotonin reuptake inhibitors and their metabolites on S-mephenytoin 4′-hydroxylase activity in human liver microsomes. Br J Clin Pharmacol 1995; 40: 481–5PubMedCrossRef
87.
Harvey AT, Preskorn SH. Fluoxetine pharmacokinetics and effect on CYP2C19 in young and elderly volunteers. J Clin Psychopharmacol 2001; 21: 161–6PubMedCrossRef
88.
Yamazaki H, Inoue K, Shaw PM, et al. Different contributions of cytochrome P450 2C19 and 3A4 in the oxidation of omeprazole by human liver microsomes: effects of contents of these two forms in individual human samples. J Pharmacol Exp Ther 1997; 283: 434–42PubMed
89.
Rasmussen BB, Nielsen TL, Brosen K. Fluvoxamine inhibits the CYP2C19-catalysed metabolism of proguanil in vitro. Eur J Clin Pharmacol 1998; 54: 735–40PubMedCrossRef
90.
Jeppesen U, Rasmussen BB, Brosen K. Fluvoxamine inhibits the CYP2C19-catalyzed bioactivation of chloroguanide. Clin Pharmacol Ther 1997; 62: 279–86PubMedCrossRef
91.
Desta Z, Soukhova NV, Flockhart DA. Inhibition of Cytochrome P450 (CYP450) isoforms by isoniazid: potent inhibition of CYP2C19 and CYP3A. Antimicrob Agents Chemother 2001; 45: 382–92PubMedCrossRef
92.
Hall SD, Guengerich FP, Branch RA, et al. Characterization and inhibition of mephenytoin 4-hydroxylase activity in human liver microsomes. J Pharmacol Exp Ther 1987; 240: 216–22PubMed
93.
Atiba JO, Blaschke TF, Wilkinson GR. Effects of ketoconazole on the polymorphic 4-hydroxylations of S-mephenytoin and debrisoquine. Br J Clin Pharmacol 1989; 28: 161–5PubMedCrossRef
94.
Ko JW, Sukhova N, Thacker D, et al. Evaluation of omeprazole and lansoprazole as inhibitors of cytochrome P450 isoforms. Drug Metab Dispos 1997; 25: 853–62PubMed
95.
Ishizaki T, Chiba K, Manabe K, et al. Comparison of the interaction potential of a new proton pump inhibitor, E3810, versus omeprazole with diazepam in extensive and poor metabolizers of S-mephenytoin 4′-hydroxylation. Clin Pharmacol Ther 1995; 58: 155–64PubMedCrossRef
96.
Caraco Y, Tateishi T, Wood AJ. Interethnic difference in omeprazole’s inhibition of diazepam metabolism. Clin Pharmacol Ther 1995; 58: 62–72PubMedCrossRef
97.
Caraco Y, Wilkinson GR, Wood AJ. Differences between white subjects and Chinese subjects in the in vivo inhibition of cytochrome P450s, 2C19, 2D6, and 3A by omeprazole. Clin Pharmacol Ther 1996; 60: 396–404PubMedCrossRef
98.
Funck-Brentano C, Becquemont L, Leneveu A, et al. Inhibition by omeprazole of proguanil metabolism: mechanism of the interaction in vitro and prediction of in vivo results from the in vitro experiments. J Pharmacol Exp Ther 1997; 280: 730–8PubMed
99.
Andersson T, Hassan-Alin M, Hasselgren G, et al. Drug interaction studies with esomeprazole, the (S)-isomer of ome-prazole. Clin Pharmacokinet 2001; 40: 523–37PubMedCrossRef
100.
Gram LF, Guentert TW, Grange S, et al. Moclobemide, a substrate of CYP2C19, and an inhibitor of CYP2C9, CYP2D6, and CYP1A2: a panel study. Clin Pharmacol Ther 1995; 57: 670–7PubMedCrossRef
101.
Laine K, Tybring G, Bertilsson L. No sex-related differences but significant inhibition by oral contraceptives of CYP2C19 activity as measured by the probe drugs mephenytoin and omeprazole in healthy Swedish white subjects. Clin Pharmacol Ther 2000; 68: 151–9PubMedCrossRef
102.
Barecki ME, Casciano CN, Johnson WW, et al. In vitro characterization of the inhibition profile of loratadine, desloratad-ine, and 3-OH-desloratadine for five human cytochrome P-450 enzymes. Drug Metab Dispos 2001; 29: 1173–5PubMed
103.
Desta Z, Park J, Soukhova N, et al. Mechanism-based inactivation of CYP2C19 and CYP2D6 by tamoxifen (TAM) and its metabolite N-desmethyltamoxifen (NDTAM) [abstract]. Clin Pharmacol Ther 2001; 69: 9
104.
Ha-Duong NT, Dijols S, Macherey AC, et al. Ticlopidine as a selective mechanism-based inhibitor of human cytochrome P450 2C19. Biochemistry 2001; 40: 12112–22PubMedCrossRef
105.
Tateishi T, Kumai T, Watanabe M, et al. Ticlopidine decreases the in vivo activity of CYP2C19 as measured by omeprazole metabolism. Br J Clin Pharmacol 1999; 47: 454–7PubMedCrossRef
106.
Mankowski DC. The role of CYP2C19 in the metabolism of (±)-bufuralol, the prototypic substrate of CYP2D6. Drug Metab Dispos 1999; 27: 1024–8PubMed
107.
Ko JW, Desta Z, Soukhova N, et al. In vitro inhibition of the cytochrome P450 (CYP) system by the antiplatelet drug ticlopidine: potent effect on CYP2C19 and CYP2D6. Br J Clin Pharmacol 2000; 49: 343–51PubMedCrossRef
108.
Levy RH. Cytochrome P450 isoenzymes and antiepileptic drug interactions. Epilepsia 1995; 36 Suppl. 5: S8–13PubMedCrossRef
109.
Inaba T, Jurima M, Mahon WA, et al. In vitro inhibition studies of two isozymes of human liver cytochrome P-450. Mephenytoin p-hydroxylase and sparteine monooxygenase. Drug Metab Dispos 1985; 13: 443–8PubMed
110.
Mather GG, Carlson S, Trager WF, et al. Prediction of zonisam-ide interactions based on metabolic isozymes [abstract]. Epilepsia 1997; 38 Suppl. 8: 108
111.
Feng HJ, Huang SL, Wang W, et al. The induction effect of rifampicin on activity of mephenytoin 4′-hydroxylase related to Ml mutation of CYP2C19 and gene dose. Br J Clin Pharmacol 1998; 45: 27–9PubMedCrossRef
112.
Zhou HH, Anthony LB, Wood AJ, et al. Induction of polymorphic 4′-hydroxylation of S-mephenytoin by rifampicin. Br J Clin Pharmacol 1990; 30: 471–5PubMedCrossRef
113.
Zilly W, Breimer DD, Richter E. Induction of drug metabolism in man after rifampicin treatment measured by increased hexobarbital and tolbutamide clearance. Eur J Clin Pharmacol 1975; 9: 219–27PubMedCrossRef
114.
Smith DA, Chandler MH, Shedlofsky SI, et al. Age-dependent stereoselective increase in the oral clearance of hexobarbitone isomers caused by rifampicin. Br J Clin Pharmacol 1991; 32: 735–9PubMed
115.
Mihara K, Svensson US, Tybring G, et al. Stereospecific analysis of omeprazole supports artemisinin as a potent inducer of CYP2C19. Fundam Clin Pharmacol 1999; 13: 671–5PubMedCrossRef
116.
Svensson US, Ashton M, Trinh NH, et al. Artemisinin induces omeprazole metabolism in human beings. Clin Pharmacol Ther 1998; 64: 160–7PubMedCrossRef
117.
Andersson T, Cederberg C, Evardsson G, et al. Effect of omeprazole treatment on diazepam plasma levels in slow versus normal rapid metabolizers of omeprazole. Clin Pharmacol Ther 1990; 47: 79–85PubMedCrossRef
118.
Schulz-Utermoehl T, Mountfield RJ, Madsen K, et al. Selective and potent inhibition of human CYP2C19 activity by a con-formationally targeted antipeptide antibody. Drug Metab Dispos 2000; 28: 715–7PubMed
119.
Waxman DJ. P450 gene induction by structurally diverse xenochemicals: central role of nuclear receptors CAR, PXR, and PPAR. Arch Biochem Biophys 1999; 369: 11–23PubMedCrossRef
120.
Fuhr U. Induction of drug metabolizing enzymes: pharmacoki-netic and toxicological consequences in humans. Clin Pharmacokinet 2000; 38: 493–504PubMedCrossRef
121.
Knodell RG, Dubey RK, Wilkinson GR, et al. Oxidative metabolism of hexobarbital in human liver: relationship to polymorphic S-mephenytoin 4-hydroxylation. J Pharmacol Exp Ther 1988; 245: 845–9PubMed
122.
Adedoyin A, Prakash C, O’Shea D, et al. Stereoselective disposition of hexobarbital and its metabolites: relationship to the S-mephenytoin polymorphism in Caucasian and Chinese subjects. Pharmacogenetics 1994; 4: 27–38PubMedCrossRef
123.
Breimer DD, Zilly W, Richter E. Influence of corticosteroid on hexobarbital and tolbutamide disposition. Clin Pharmacol Ther 1978; 24: 208–12PubMed
124.
Branch RA, Adedoyin A, Frye RF, et al. In vivo modulation of CYP enzymes by quinidine and rifampin. Clin Pharmacol Ther 2000; 68: 401–11PubMedCrossRef
125.
Dickinson RG, Hooper WD, Patterson M, et al. Extent of urinary excretion of p-hydroxyphenytoin in healthy subjects given phenytoin. Ther Drug Monit 1985; 7: 283–9PubMedCrossRef
126.
Fritz S, Lindner W, Roots I, et al. Stereochemistry of aromatic phenytoin hydroxylation in various drug hydroxylation phe-notypes in humans. J Pharmacol Exp Ther 1987; 241: 615–22PubMed
127.
Ieiri I, Mamiya K, Urae A, et al. Stereoselective 4′-hydroxylation of phenytoin: relationship to (S)-mephenytoin polymorphism in Japanese. Br J Clin Pharmacol 1997; 43: 441–5PubMedCrossRef
128.
Bertilsson L, Tybring G, Widen J, et al. Carbamazepine treatment induces the CYP3A catalyzed sulfoxidation of omeprazole, but has no or less effect on hydroxylation via CYP2C19. Br J Clin Pharmacol 1997; 44: 186–9PubMedCrossRef
129.
Hadama A, Ieiri I, Morita T, et al. P-hydroxylation of phenobar-bital: relationship to (S)-mephenytoin hydroxylation (CYP-2C19) polymorphism. Ther Drug Monit 2001; 23: 115–8PubMedCrossRef
130.
Zhao X, Rae J, Flockhart DA. Cloning and sequencing of 5′-regulatory region of CYP2C19 [abstract]. Clin Pharmacol Ther 2001; 69(2): P72
131.
Adedoyin A, Arns PA, Richards WO, et al. Selective effect of liver disease on the activities of specific metabolizing enzymes: investigation of cytochromes P450 2C19 and 2D6. Clin Pharmacol Ther 1998; 64: 8–17PubMedCrossRef
132.
Andersson T, Olsson R, Regardh CG, et al. Pharmacokinetics of [14C]omeprazole in patients with liver cirrhosis. Clin Pharmacokinet 1993; 24: 71–8PubMedCrossRef
133.
Rost KL, Brockmoller J, Esdorn F, et al. Phenocopies of poor metabolizers of omeprazole caused by liver disease and drug treatment. J Hepatol 1995; 23: 268–77PubMed
134.
Khaliq Y, Gallicano K, Seguin I, et al. Single and multiple dose pharmacokinetics of nelfinavir and CYP2C19 activity in hu-man immunodeficiency virus-infected patients with chronic liver disease. Br J Clin Pharmacol 2000; 50: 108–15PubMedCrossRef
135.
Arns PA, Adedoyin A, DiBisceglie AM, et al. Mephenytoin disposition and serum bile acids as indices of hepatic function in chronic viral hepatitis. Clin Pharmacol Ther 1997; 62: 527–37PubMedCrossRef
136.
Williams ML, Bhargava P, Cherrouk I, et al. A discordance of the cytochrome P450 2C19 genotype and phenotype in patients with advanced cancer. Br J Clin Pharmacol 2000; 49: 485–8PubMedCrossRef
137.
Flockhart DA, Clauw DJ, Sale EB, et al. Pharmacogenetic characteristics of the eosinophilia-myalgia syndrome. Clin Pharmacol Ther 1994; 56: 398–405PubMedCrossRef
138.
Pollock BG, Perel JM, Kirshner M, et al. S-Mephenytoin 4-hy-droxylation in older Americans. Eur J Clin Pharmacol 1991; 40: 609–11PubMed
139.
Hagg S, Spigset O, Dahlqvist R. Influence of gender and oral contraceptives on CYP2D6 and CYP2C19 activity in healthy volunteers. Br J Clin Pharmacol 2001; 51: 169–73PubMedCrossRef
140.
Xie HG, Huang ZH, Xiao ZS, et al. Evidence for the effect of gender on activity of (S)-mephenytoin 4′-hydroxylase (CYP-2C19) in a Chinese population. Pharmacogenetics 1997; 7: 115–9PubMedCrossRef
141.
Lewis DF, Dickins M, Weaver RJ, et al. Molecular modeling of human 2C subfamily enzymes CYP2C9 and CYP2C19: rationalization of substrate specificity and site-directed muta-genesis experiments in the CYP2C subfamily. Xenobiotica 1998; 28: 235–68PubMedCrossRef
142.
Bertilsson L, Henthorn TK, Sanz EJ, et al. Importance of genetic factor in the regulation of diazepam metabolism: relationship to S-mephenytoin, but not debrisoquin, hydroxylation phenotype. Clin Pharmacol Ther 1989; 45: 348–55PubMedCrossRef
143.
Wan J, Xia H, He N, et al. The elimination of diazepam in Chinese subjects is dependent on the mephenytoin oxidation phenotype. Br J Clin Pharmacol 1996; 42: 471–4PubMedCrossRef
144.
Helsby NA, Ward SA, Edwards G, et al. The pharmacokinetics and activation of proguanil in man: consequences of variability in drug metabolism. Br J Clin Pharmacol 1990; 30: 593–8PubMedCrossRef
145.
Lillibridge JH, Lee CA, Pithavala YK, et al. The role of CYP2C19 in the formation of nelfinavir hydroxy-t-butylam-ide (M8): in vitro/in vivo correlation [abstract]. ISSX Proceedings 1998; 13: 119
146.
Yamazaki H, Shimada T. Progesterone and testosterone hydroxylation by cytochromes p450 2cl9, 2c9, and 3a4 in human liver microsomes. Arch Biochem Biophys 1997; 346: 161–9PubMedCrossRef
147.
Stresser DM, Kupfer D. Human cytochrome P450-catalyzed conversion of the proestrogenic pesticide methoxychlor into an estrogen: role of CYP2C19 and CYP1A2 in O-demethyl-ation. Drug Metab Dispos 1998; 26: 868–74PubMed
148.
Kilicarslan T, Haining RL, Rettie AE, et al. Flunitrazepam metabolism by cytochrome P450s 2C19 and 3A4. Drug Metab Dispos 2001; 29: 460–5PubMed
149.
Liu ZQ, Cheng ZN, Huang SL, et al. Effect of the CYP2C19 oxidation polymorphism on fluoxetine metabolism in Chinese healthy subjects. Br J Clin Pharmacol 2001; 52: 96–9PubMedCrossRef
150.
Wang JH, Liu ZQ, Wang W, et al. Pharmacokinetics of sertral-ine in relation to genetic polymorphism of CYP2C19. Clin Pharmacol Ther 2001; 70: 42–7PubMedCrossRef
151.
Lind T, Andersson T, Skanberg I, et al. Biliary excretion of intravenous [14C]omeprazole in humans. Clin Pharmacol Ther 1987; 42: 504–8PubMedCrossRef
152.
Chiba K, Kobayashi K, Manabe K, et al. Oxidative metabolism of omeprazole in human liver microsomes: consegregation with S-mephenytoin 4′-hydroxylation. J Pharmacol Exp Ther 1993; 266: 52–9PubMed
153.
Pichard L, Curi-Pedrosa R, Bonfils C, et al. Oxidative metabolism of lansoprazole by human liver cytochromes P450. Mol Pharmacol 1995; 47: 410–8PubMed
154.
Sohn DR, Kwon JT, Kim HK, et al. Metabolic disposition of lansoprazole in relation to the S-mephenytoin 4′-hydroxylation phenotype status. Clin Pharmacol Ther 1997; 61: 574–82PubMedCrossRef
155.
Andersson T. Pharmacokinetics, metabolism and interactions of acid pump inhibitors: focus on omeprazole, lansoprazole and pantoprazole. Clin Pharmacokinet 1996; 31: 9–28PubMedCrossRef
156.
Yasuda SU, Horai Y, Tomono Y, et al. Comparison of the kinetic disposition and metabolism of E3810, a new proton pump inhibitor, and omeprazole in relation to S-mephenytoin 4′-hydroxylation status. Clin Pharmacol Ther 1995; 58: 143–54PubMedCrossRef
157.
VandenBranden M, Ring BJ, Binkley SN, et al. Interaction of human liver cytochromes P450 in vitro with LY307640, a gastric proton pump inhibitor. Pharmacogenetics 1996; 6: 81–91PubMedCrossRef
158.
Komatsu T, Yamazaki H, Asahi S, et al. Formation of a dihy-droxy metabolite of phenytoin in human liver microsomes/cy-tosol: roles of cytochromes P450, 2C9, 2C19, and 3A4. Drug Metab Dispos 2000; 28(11): 1361–8PubMed
159.
Kupfer A, Patwardhan R, Ward SA, et al. Stereoselective metabolism and pharmacogenetic control of 5-phenyl-5-ethyl-hydantoin (nirvanol) in humans. J Pharmacol Exp Ther 1984; 230: 28–33PubMed
160.
Schellens JH, van der Wart JH, Breimer DD. Relationship between mephenytoin oxidation polymorphism and phenytoin, methylphenytoin and phenobarbitone hydroxylation assessed in a phenotyped panel of healthy subjects. Br J Clin Pharmacol 1990; 29: 665–71PubMedCrossRef
161.
Andersson T, Miners JO, Veronese ME, et al. Diazepam metabolism by human liver microsomes is mediated by both S-mephenytoin hydroxylase and CYP3A isoforms. Br J Clin Pharmacol 1994; 38: 131–7PubMedCrossRef
162.
Yasumori T, Nagata K, Yang SK, et al. Cytochrome P450 medicated metabolism of diazepam in human and rat: involvement of human CYP2C in N-demethylation in the substrate concentration-dependent manner. Pharmacogenetics 1993; 3: 291–301PubMedCrossRef
163.
Coller JK, Somogyi AA, Bochner F. Flunitrazepam oxidative metabolism in human liver microsomes: involvement of CYP2C19 and CYP3A4. Xenobiotica 1999; 29: 973–86PubMedCrossRef
164.
Mamiya K, Hadama A, Yukawa E, et al. CYP2C19 polymorphism effect on phenobarbitone: pharmacokinetics in Japanese patients with epilepsy: analysis by population pharmacokinetics. Eur J Clin Pharmacol 2000; 55: 821–5PubMedCrossRef
165.
Yasumori T, Murayama N, Yamazoe Y, et al. Polymorphism in hydroxylation of mephenytoin and hexobarbital stereoiso-mers in relation to hepatic P-450 human-2. Clin Pharmacol Ther 1990; 47: 313–22PubMedCrossRef
166.
Kupfer A, Branch RA. Steroselective mephobarbital hydroxylation cosegregates with mephenytoin hydroxylation. Clin Pharmacol Ther 1985; 38: 414–8PubMedCrossRef
167.
Kobayashi K, Kogo M, Tani M, et al. Role of CYP2C19 in stereoselective hydroxylation of mephobarbital by human liver microsomes. Drug Metab Dispos 2001; 29: 36–40PubMed
168.
Olsen H, Koppang E, Alvan G, et al. Carisoprodol elimination in humans. Ther Drug Monit 1994; 16: 337–40PubMedCrossRef
169.
Dalen P, Alvan G, Wakelkamp M, et al. Formation of mepro-bamate from carisoprodol is catalysed by CYP2C19. Pharma-cogenetics 1996; 6(5): 387–94
170.
Partovian C, Jacqz-Aigrain E, Keundjian A, et al. Comparison of chloroguanide and mephenytoin for the in vivo assessment of genetically determined CYP2C19 activity in humans. Clin Pharmacol Ther 1995; 58: 257–63PubMedCrossRef
171.
Helsby NA, Ward SA, Howells RE, et al. In vitro metabolism of the biguanide antimalarials in human liver microsomes: evidence for a role of the mephenytoin hydroxylase (P450 MP) enzyme. Br J Clin Pharmacol 1990; 30: 287–91PubMedCrossRef
172.
Birkett DJ, Rees DL, Andersson T, et al. In vitro proguanil activation to cycloguanil by human liver microsomes is mediated by CYP3A isoforms as well as by S-mephenytoin hydroxylase. Br J Clin Pharmacol 1994; 37: 413–20PubMedCrossRef
173.
Wright JD, Helsby NA, Ward SA. The role of S-mephenytoin hydroxylase (CYP2C19) in the metabolism of the antimalar-ial biguanides. Br J Clin Pharmacol 1995; 39: 441–4PubMedCrossRef
174.
Sindrup SH, Brosen K, Hansen MG, et al. Pharmacokinetics of citalopram in relation to the sparteine and the mephenytoin oxidation polymorphisms. Ther Drug Monit 1993; 15: 11–7PubMedCrossRef
175.
Fukuda T, Yamamoto I, Nishida Y, et al. Effect of the CYP2D6*10 genotype on venlafaxine pharmacokinetics in healthy adult volunteers. Br J Clin Pharmacol 1999; 47: 450–3PubMedCrossRef
176.
Skjelbo E, Brosen K, Hallas J, et al. The mephenytoin oxidation polymorphism is partially responsible for the N-demethylation of imipramine. Clin Pharmacol Ther 1991; 49: 18–23PubMedCrossRef
177.
Skjelbo E, Gram LF, Brosen K. The N-demethylation of imipramine correlates with the oxidation of S-mephenytoin (S/R-ratio): a population study. Br J Clin Pharmacol 1993; 35: 331–4PubMed
178.
Koyama E, Sohn DR, Shin SG, et al. Metabolic disposition of imipramine in oriental subjects: relation to metoprolol alpha-hydroxylation and S-mephenytoin 4′-hydroxylation pheno-types. J Pharmacol Exp Ther 1994; 271: 860–7PubMed
179.
Nielsen KK, Brosen K, Hansen MG, et al. Single-dose kinetics of clomipramine: relationship to the sparteine and S-mephenytoin oxidation polymorphisms. Clin Pharmacol Ther 1994; 55: 518–27PubMedCrossRef
180.
Eap CB, Bender S, Gastpar M, et al. Steady state plasma levels of the enantiomers of trimipramine and of its metabolites in CYP2D6-, CYP2C19- and CYP3A4/5-phenotyped patients. Ther Drug Monit 2000; 22: 209–14PubMedCrossRef
181.
Breyer-Pfaff U, Pfandl B, Nill K, et al. Enantioselective ami-triptyline metabolism in patients phenotyped for two cyto-chrome P450 isozymes. Clin Pharmacol Ther 1992; 52: 350–8PubMedCrossRef
182.
Olesen OV, Linnet K. Hydroxylation and demethylation of the tricyclic antidepressant nortriptyline by cDNA-expressed human cytochrome P-450 isozymes. Drug Metab Dispos 1997; 25: 740–4PubMed
183.
Eap CB, Guentert TW, Schaublin-Loidl M, et al. Plasma levels of the enantiomers of thioridazine, thioridazine 2-sulfoxide, thioridazine 2-sulfone, and thioridazine 5-sulfoxide in poor and extensive metabolizers of dextromethorphan and mephenytoin. Clin Pharmacol Ther 1996; 59: 322–31PubMedCrossRef
184.
Ward SA, Walle T, Walle UK, et al. Propanolol’s metabolism is determined by both mephenytoin and debrisoquin hydroxylase activities. Clin Pharmacol Ther 1989; 45: 72–9PubMedCrossRef
185.
Lasker JM, Wester MR, Aramsombatdee E, et al. Characterization of cyp2c19 and cyp2c9 from human liver: respective roles in microsomal tolbutamide, S-mephenytoin, and omeprazole hydroxylations. Arch Biochem Biophys 1998; 353: 16–28PubMedCrossRef
186.
Wienkers LC, Wurden CJ, Storch E, et al. Formation of (R)-8-hydroxywarfarin in human liver microsomes: a new metabolic marker for the (S)-mephenytoin hydroxylase, P4502C19. Drug Metab Dispos 1996; 24: 610–4PubMed
187.
Cheng ZN, Shu Y, Liu ZQ, et al. Role of cytochrome P450 in estradiol metabolism in vitro. Acta Pharmacol Sin 2001; 22: 148–54PubMed
188.
Gentile DM, Verhoeven CH, Shimada T, et al. The role of CYP2C in the in vitro bioactivation of the contraceptive steroid desogestrel. J Pharmacol Exp Ther 1998; 287: 975–82PubMed
189.
Chang TK, Yu L, Goldstein JA, et al. Identification of the poly-morphically expressed CYP2C19 and the wild-type CYP2C9-ILE359 allele as low-Km catalysts of cyclophosph-amide and ifosfamide activation. Pharmacogenetics 1997; 7: 211–21PubMedCrossRef
190.
Kivisto KT, Kroemer HK, Eichelbaum M. The role of human cytochrome P450 enzymes in the metabolism of anticancer agents; implications for drug interactions. Br J Clin Pharmacol 1995; 40: 523–30PubMedCrossRef
191.
Schepp W. Proton pump inhibitory therapy: then and now. Yale J Biol Med 1996; 69: 175–86PubMed
192.
Sachs G, Shin JM, Briving C, et al. The pharmacology of the gastric acid pump: the H+, K+ ATPase. Annu Rev Pharmacol Toxicol 1995; 35: 277–305PubMedCrossRef
193.
Thomson AB. Are the orally administered proton pump inhibitors equivalent?: a comparison of lansoprazole, omeprazole, pantoprazole, and rabeprazole. Curr Gastroenterol Rep 2000; 2: 482–93PubMedCrossRef
194.
Andersson T, Miners JO, Veronese ME, et al. Identification of human liver cytochrome P450 isoforms mediating omeprazole metabolism. Br J Clin Pharmacol 1993; 36: 521–30PubMedCrossRef
195.
Abelo A, Andersson TB, Antonsson M, et al. Stereoselective metabolism of omeprazole by human cytochrome P450 enzymes. Drug Metab Dispos 2000; 28: 966–72PubMed
196.
Pearce RE, Rodrigues AD, Goldstein JA, et al. Identification of the human P450 enzymes involved in lansoprazole metabolism. J Pharmacol Exp Ther 1996; 277: 805–16PubMed
197.
Andersson T, Miners JO, Veronese ME, et al. Identification of human liver cytochrome P450 isoforms mediating secondary omeprazole metabolism. Br J Clin Pharmacol 1994; 37: 597–604PubMedCrossRef
198.
Klotz U. Pharmacokinetic considerations in the eradication of Helicobacter pylori. Clin Pharmacokinet 2000; 38: 243–70PubMedCrossRef
199.
Andersson T, Hassan-Alin M, Hasselgren G, et al. Pharmacokinetic studies with esomeprazole, the (S)-isomer of omeprazole. Clin Pharmacokinet 2001; 40: 411–26PubMedCrossRef
200.
Tybring G, Bottiger Y, Widen J, et al. Enantioselective hydroxylation of omeprazole catalyzed by CYP2C19 in Swedish white subjects. Clin Pharmacol Ther 1997; 62: 129–37PubMedCrossRef
201.
Katsuki H, Yagi H, Arimori K, et al. Determination of R(+)-and S(-)-lansoprazole using chiral stationary-phase liquid chromatography and their enantioselective pharmacokinetics in humans. Pharm Res 1996; 13(4): 611–5PubMedCrossRef
202.
Tanaka M, Ohkubo T, Otani K, et al. Stereoselective pharmacokinetics of pantoprazole, a proton pump inhibitor, in extensive and poor metabolizers of S-mephenytoin. Clin Pharmacol Ther 2001; 69: 108–13PubMedCrossRef
203.
Regardh CG, Andersson T, Lagerstrom PO, et al. The pharmacokinetics of omeprazole in humans: a study of single intravenous and oral doses. Ther Drug Monit 1990; 12: 163–72PubMedCrossRef
204.
Andersson T, Holmberg J, Rohss K, et al. Pharmacokinetics and effect on caffeine metabolism of the proton pump inhibitors, omeprazole, lansoprazole, and pantoprazole. J Clin Pharmacol 1998; 45: 369–75
205.
Zhou Q, Yamamoto I, Fukuda T, et al. CYP2C19 genotypes and omeprazole metabolism after single and repeated dosing when combined with clarithromycin. Eur J Clin Pharmacol 1999; 55: 43–7PubMedCrossRef
206.
Chang M, Tybring G, Dahl ML, et al. Interphenotype differences in disposition and effect on gastrin levels of omeprazole-suitability of omeprazole as a probe for CYP2C19. Br J Clin Pharmacol 1995; 39: 511–8PubMedCrossRef
207.
Furuta T, Ohashi K, Kosuge K, et al. CYP2C19 genotype status and effect of omeprazole on intragastric pH in humans. Clin Pharmacol Ther 1999; 65: 552–61PubMedCrossRef
208.
Sagar M, Bertilsson L, Stridsberg M, et al. Omeprazole and CYP2C19 polymorphism: effects of long-term treatment on gastrin, pepsinogen I, and chromogranin A in patients with acid related disorders. Aliment Pharmacol Ther 2000; 14: 1495–502PubMedCrossRef
209.
Furuta T, Ohashi K, Kamata T, et al. Effect of genetic differences in omeprazole metabolism on cure rates for Helicobac-ter pylori infection and peptic ulcer. Ann Intern Med 1998; 129: 1027–30PubMed
210.
Aoyama N, Tanigawara Y, Kita T, et al. Sufficient effect of 1-week omeprazole and amoxicillin dual treatment for Helicobacter pylori eradication in cytochrome P450 2C19 poor metabolizers. J Gastroenterol 1999; 34 Suppl. 11: 80–3PubMed
211.
Tanigawara Y, Aoyama N, Kita T, et al. CYP2C19 genotype-related efficacy of omeprazole for the treatment of infection caused by Helicobacter pylori. Clin Pharmacol Ther 1999; 66: 528–34PubMedCrossRef
212.
Furuta T, Takashima M, Shirai N, et al. Cure of refractory duodenal ulcer and infection caused by Helicobacter pylori by high doses of omeprazole and amoxicillin in a homozygous CYP2C19 extensive metabolizer patient. Clin Pharmacol Ther 2000; 67: 684–9PubMedCrossRef
213.
Adachi K, Katsube T, Kawamura A, et al. CYP2C19 genotype status and intragastric pH during dosing with lansoprazole or rabeprazole. Aliment Pharmacol Ther 2000; 14: 1259–66PubMedCrossRef
214.
Furuta T, Shirai N, Takashima M, et al. Effects of genotypic differences in CYP2C19 status on cure rates for Helicobacter pylori infection by dual therapy with rabeprazole plus amoxicillin. Pharmacogenetics 2001; 11: 341–8PubMedCrossRef
215.
Hokari K, Sugiyama T, Kato M, et al. Efficacy of triple therapy with rabeprazole for Helicobacter pylori infection and CYP2C19 genetic polymorphism. Aliment Pharmacol Ther 2001; 15: 1479–84PubMedCrossRef
216.
Furuta T, Ohashi K, Kobayashi K, et al. Effects of clarithromycin on the metabolism of omeprazole in relation to CYP2C19 genotype status in humans. Clin Pharmacol Ther 1999; 66: 265–74PubMedCrossRef
217.
Bottiger Y, Tybring G, Gotharson E, et al. Inhibition of the sulfoxidation of omeprazole by ketoconazole in poor and extensive metabolizers of S-mephenytoin. Clin Pharmacol Ther 1997; 62: 384–91PubMedCrossRef
218.
Moore LB, Goodwin B, Jones SA, et al. St. John’s wort induces hepatic drug metabolism through activation of the pregnane X receptor. Proc Natl Acad Sci U S A 2000; 97: 7500–2PubMedCrossRef
219.
Moore JT, Kliewer SA. Use of the nuclear receptor PXR to predict drug interactions. Toxicology 2000; 153: 1–10PubMedCrossRef
220.
Lefebvre RA, Flouvat B, Karolac-Tamisier S, et al. Influence of lansoprazole on diazepam plasma concentrations. Clin Pharmacol Ther 1992; 52: 458–63PubMedCrossRef
221.
Zomorodi K, Houston JB. Diazepam-omeprazole inhibition interaction: an in vitro investigation using liver microsomes. Br J Clin Pharmacol 1996; 42: 157–62PubMedCrossRef
222.
Gugler R, Jensen JC. Omeprazole inhibits oxidative drug metabolism: studies with diazepam and phenytoin in vivo and 7-ethoxycoumarin in vitro. Gastroenterology 1985; 89: 1235–41PubMed
223.
Prichard PJ, Walt RP, Kitchingman KW, et al. Oral phenytoin pharmacokinetics during omeprazole therapy. Br J Clin Pharmacol 1987; 24: 543–5PubMedCrossRef
224.
Suri A, Bramer SL. Effect of omeprazole on the metabolism of cilostazol. Clin Pharmacokinet 1999; 37 Suppl. 2: 53–9PubMedCrossRef
225.
Rost KL, Brosicke H, Heinemeyer G, et al. Specific and dose-dependent enzyme induction by omeprazole in human beings. Hepatology 1994; 20: 1204–12PubMedCrossRef
226.
Dixit RK, Chawla AB, Kumar N, et al. Effect of omeprazole on the pharmacokinetics of sustained-release carbamazepine in healthy male volunteers. Methods Find Exp Clin Pharmacol 2001; 23: 37–9PubMedCrossRef
227.
Diaz D, Fabre I, Daujat M, et al. Omeprazole is an aryl hydrocarbon-like inducer of human hepatic cytochrome P450. Gastroenterology 1990; 99: 737–47PubMed
228.
Rost KL, Brosicke H, Scheffler M, et al. Dose dependent induction of CYP1A2 activity by omeprazole (Antra). Int J Clin Pharmacol TherToxicol 1992; 30: 542–3
229.
Fuhr U, Rost KL. Simple and reliable CYP1A2 phenotyping by the paraxanthine/caffeine ratio in plasma and in saliva. Pharmacogenetics 1994; 4: 109–16PubMedCrossRef
230.
Rost KL, Roots I. Accelerated caffeine metabolism after omeprazole treatment is indicated by urinary metabolic ratios: coincidence with plasma clearance and breath test. Clin Pharmacol Ther 1994; 55: 402–11PubMedCrossRef
231.
Nousbaum JB, Berthou F, Carlhant D, et al. Four-week treatment with omeprazole increases the metabolism of caffeine. Am J Gastroenterol 1994; 89: 371–5PubMed
232.
Steinijans VW, Huber R, Hartmann M, et al. Lack of pantoprazole drug interactions in man: an updated review. Int J Clin Pharmacol Ther 1996; 34: 243–62PubMed
233.
Kim KA, Shon JH, Park JY, et al. Enantioselective disposition of lansoprazole in extensive and poor metabolizers of CYP2C19. Clin Pharmacol Ther 2000; 72: 90–9CrossRef
234.
Dilger K, Zheng Z, Klotz U. Lack of drug interaction between omeprazole, lansoprazole, pantoprazole and theophylline. Br J Clin Pharmacol 1999; 48: 438–44PubMedCrossRef
235.
Taubert AM, Geneve J, Bocquentin M, et al. Theophylline steady state pharmacokinetics is not altered by omeprazole. Eur J Clin Pharmacol 1992; 42: 343–5
236.
Ko JW, Jang IJ, Shin JG, et al. Theophylline pharmacokinetics are not altered by lansoprazole in CYP2C19 poor metabolizers. Clin Pharmacol Ther 1999; 65: 606–14PubMedCrossRef
237.
Howden CW. Vitamin B12 levels during prolonged treatment with proton pump inhibitors. J Clin Gastroenterol 2000; 30: 29–33PubMedCrossRef
238.
Sagar M, Janczewska I, Ljungdahl A, et al. Effect of CYP2C19 polymorphism on serum levels of vitamin B12 in patients on long-term omeprazole treatment. Aliment Pharmacol Ther 1999; 13: 453–8PubMedCrossRef
239.
Bellou A, Aimone-Gastin I, De Korwin JD, et al. Cobalamin deficiency with megaloblastic anemia in one patient under long-term omeprazole therapy. J Intern Med 1996; 240: 161–4PubMedCrossRef
240.
Chen S, Chou WH, Blouin RA, et al. The cytochrome P450 2D6 (CYP2D6) enzyme polymorphism: screening costs and influence on clinical outcomes in psychiatry. Clin Pharmacol Ther 1996; 60: 522–34PubMedCrossRef
241.
Pfost DR, Boyce-Jacino MT, Grant DM. A SNPshot: pharma-cogenetics and the future of drug therapy. Trends Biotechnol 2000; 18: 334–8PubMedCrossRef
242.
Flockhart DA, Webb DJ. Clinical pharmacology: blue-chip technology. Lancet 1998; 352 Suppl. 4: SIV2PubMed
243.
Amerisource Corporation. Average wholesales prices of drugs. Valley Forge (PA): Amerisource Corporation, 2001
244.
Mandelli M, Tognoni G, Garattini S. Clinical pharmacokinetics of diazepam. Clin Pharmacokinet 1978; 3: 72–91PubMedCrossRef
245.
Greenblatt DJ, Allen MD, Harmatz JS, et al. Diazepam disposition determinants. Clin Pharmacol Ther 1980; 27: 301–12PubMedCrossRef
246.
Jung F, Richardson TH, Raucy JL, et al. Diazepam metabolism by cDNA-expressed human 2C P450s: identification of P4502C18 and P4502C19 as low KM diazepam N-demethyl-ases. Drug Metab Dispos 1997; 25: 133–9PubMed
247.
Yasumori T, Li QH, Yamazoe Y, et al. Lack of low Km diazepam N-demethylase in livers of poor metabolizers for S-mephenytoin 4′-hydroxylation. Pharmacogenetics 1994; 4: 323–31PubMedCrossRef
248.
Kato R, Yamazoe Y. The importance of substrate concentration in determining cytochromes P450 therapeutically relevant in vivo. Pharmacogenetics 1994; 4: 359–62PubMedCrossRef
249.
Bertilsson L, Kalow W. Why are diazepam metabolism and polymorphic S-mephenytoin hydroxylation associated with each other in white and Korean populations but not in Chinese populations?. Clin Pharmacol Ther 1993; 53: 608–10PubMedCrossRef
250.
Qin XP, Xie HG, Wang W, et al. Effect of the gene dosage of CYP2C19 on diazepam metabolism in Chinese subjects. Clin Pharmacol Ther 1999; 66: 642–6PubMed
251.
Kumana CR, Lauder IJ, Chan M, et al. Differences in diazepam pharmacokinetics in Chinese and white Caucasians: relation to body lipid stores. Eur J Clin Pharmacol 1987; 32: 211–5PubMedCrossRef
252.
Greenblatt DJ, Abernethy DR, Morse DS, et al. Clinical importance of the interaction of diazepam and cimetidine. N Engl J Med 1984; 310: 1639–43PubMedCrossRef
253.
Lemberger L, Rowe H, Bosomworth JC, et al. The effect of fluoxetine on the pharmacokinetics and psychomotor responses of diazepam. Clin Pharmacol Ther 1998; 63: 412–9
254.
Dent LA, Orrock MW. Warfarin-fluoxetine and diazepam-fluoxetine interaction. Pharmacotherapy 1997; 17: 170–2PubMed
255.
Ochs HR, Greenblatt DJ, Roberts GM, et al. Diazepam interaction with antituberculosis drugs. Clin Pharmacol Ther 1981; 29: 671–8PubMedCrossRef
256.
Klotz U, Reimann I. Elevation of steady-state diazepam levels by cimetidine. Clin Pharmacol Ther 1981; 30: 513–7PubMedCrossRef
257.
Gugler R, Hartmann M, Rudi J, et al. Lack of pharmacokinetic interaction of pantoprazole with diazepam in man. Br J Clin Pharmacol 1996; 42: 249–52PubMedCrossRef
258.
Gardner MJ, Baris BA, Wilner KD, et al. Effect of sertraline on the pharmacokinetics and protein binding of diazepam in healthy volunteers. Clin Pharmacokinet 1997; 32 Suppl. 1: 43–9PubMedCrossRef
259.
Ohnhaus EE, Brockmeyer N, Dylewicz P, et al. The effect of antipyrine and rifampin on the metabolism of diazepam. Clin Pharmacol Ther 1987; 42: 148–56PubMedCrossRef
260.
Spina E, Buemi AL, Sanz EJ, et al. Diazepam treatment does not influence the debrisoquine or mephenytoin hydroxylation phenotyping tests. Ther Drug Monit 1989; 11: 721–3PubMedCrossRef
261.
Otani K, Nordin C, Bertilsson L. No interaction of diazepam on amitriptyline disposition in depressed patients. Ther Drug Monit 1987; 9: 120–2PubMedCrossRef
262.
Schmider J, Greenblatt DJ, von Moltke LL, et al. Relationship of in vitro data on drug metabolism to in vivo pharmacokinetics and drug interactions: implications for diazepam disposition in humans. J Clin Psychopharmacol 1996; 16: 267–72PubMedCrossRef
263.
Ruffalo RL, Thompson JF, Segal JL. Diazepam-cimetidine drug interaction: a clinically significant effect. South Med J 1981; 74: 1075–8PubMedCrossRef
264.
Nation RL, Evans AM, Milne RW. Pharmacokinetic drug interactions with phenytoin (Part I). Clin Pharmacokinet 1990; 18: 37–60PubMedCrossRef
265.
Nation RL, Evans AM, Milne RW. Pharmacokinetic drug interactions with phenytoin (Part II). Clin Pharmacokinet 1990; 18: 131–50PubMedCrossRef
266.
Miners JO, Birkett DJ. Cytochrome P4502C9: an enzyme of major importance in human drug metabolism. Br J Clin Pharmacol 1998; 45: 525–38PubMedCrossRef
267.
Bajpai M, Roskos LK, Shen DD, et al. Roles of cytochrome P4502C9 and cytochrome P4502C19 in the stereoselective metabolism of phenytoin to its major metabolite. Drug Metab Dispos 1996; 24: 1401–3PubMed
268.
Yasumori T, Chen LS, Li QH, et al. Human CYP2C-mediated stereoselective phenytoin hydroxylation in Japanese: difference in chiral preference of CYP2C9 and CYP2C19. Biochem Pharmacol 1999; 57: 1297–303PubMedCrossRef
269.
Shiimada T, Misono KS, Guengerich FP. Human liver micro-somal cytochrome P-450 mephenytoin 4-hydroxylase, a prototype of genetic polymorphism in oxidative drug metabolism. J Biol Chem 1985; 261: 909–21
270.
Odani A, Hashimoto Y, Otsuki Y, et al. Genetic polymorphism of the CYP2C subfamily and its effect on the pharmacokinetics of phenytoin in Japanese patients with epilepsy. Clin Pharmacol Ther 1997; 62: 287–92PubMedCrossRef
271.
Mamiya K, Ieiri I, Shimamato J, et al. The effects of genetic polymorphisms of CYP2C9 and CYP2C19 on phenytoin metabolism in Japanese adult patients with epilepsy: studies in stereoselective hydroxylation and population pharmacokinetics. Epilepsia 1998; 39: 1317–23PubMedCrossRef
272.
Watanabe M, Iwahashi K, Kugoh T, et al. The relationship between phenytoin pharmacokinetics and the cyp2cl9 genotype in Japanese epileptic patients. Clin Neuropharmacol 1998; 21: 122–6PubMed
273.
Privitera M, Welty TE, et al. Acute phenytoin toxicity followed by seizure breakthrough from a ticlopidine-phenytoin interaction. Arch Neurol 1996; 53: 1191–2PubMedCrossRef
274.
Donahue S, Flockhart DA, Abernethy DR. Ticlopidine inhibits phenytoin clearance. Clin Pharmacol Ther 1999; 66: 563–8PubMed
275.
Donahue SR, Flockhart DA, Abernethy DR, et al. Ticlopidine inhibition of phenytoin metabolism mediated by potent inhibition of CYP2C19. Clin Pharmacol Ther 1997; 62: 572–7PubMedCrossRef
276.
Gidal BE, Sorkness CA, McGill KA, et al. Evaluation of a potential enantioselective interaction between ticlopidine and warfarin in chronically anticoagulated patients. Ther Drug Monit 1995; 17: 33–8PubMedCrossRef
277.
Masimirembwa CM, Otter C, Berg M, et al. Heterologous expression and kinetic characterization of human cytochromes P-450: validation of a pharmaceutical tool for drug metabolism research. Drug Metab Dispos 1999; 27: 1117–22PubMed
278.
Self TH, Chrisman CR, Baciewicz AM, et al. Isoniazid drug and food interactions. Am J Med Sci 1999; 317: 304–11PubMedCrossRef
279.
Gisclon LG, Curtin CR, Kramer LD. The steady-state (SS) pharmacokinetics (PK) of phenytoin (Dilantin) and topira-mate (Topamax) in epileptic patients on monotherapy, and during combination therapy [abstract]. Epilepsia 1994; 35 Suppl. 8: 54
280.
Andersson T, Lagerstrom PO, Unge P. A study of the interaction between omeprazole and phenytoin in epileptic patients. TherDrug Monit 1990; 12: 329–33CrossRef
281.
Sachdeo R, Padela MF. The effect of felbamate on phenobarbital serum concentrations [abstract]. Epilepsia 1994; 35 Suppl. 8: 94CrossRef
282.
Odani A, Hashimoto Y, Takayanagi K, et al. Population pharmacokinetics of phenytoin in Japanese patients with epilepsy: analysis with a dose-dependent clearance model. Biol Pharm Bull 1996; 19: 444–8PubMedCrossRef
283.
Pisani F, Fazio A, Artesi C, et al. Elevation of plasma phenytoin by viloxazine in epileptic patients: a clinically significant drug interaction. J Neurol Neurosurg Psychiatry 1992; 55: 126–7PubMedCrossRef
284.
Aynacioglu AS, Brockmoller J, Bauer S, et al. Frequency of cytochrome P450 CYP2C9 variants in a Turkish population and functional relevance for phenytoin. Br J Clin Pharmacol 1999; 48: 409–15PubMedCrossRef
285.
Riva R, Albani F, Contin M, et al. Pharmacokinetic interactions between antiepileptic drugs: clinical considerations. Clin Pharmacokinet 1996; 31: 470–93PubMedCrossRef
286.
Anderson GD. A mechanistic approach to antiepileptic drug interactions. Ann Pharmacother 1998; 32: 554–63PubMedCrossRef
287.
Gidal BE, Zupanc ML. Potential pharmacokinetic interaction between felbamate and phenobarbital. Ann Pharmacother 1994; 28: 455–8PubMed
288.
Reidenberg P, Glue P, Banfield CR, et al. Effects of felbamate on the pharmacokinetics of phenobarbital. Clin Pharmacol Ther 1995; 58: 279–87PubMedCrossRef
289.
Elenbaas JK. Centrally acting oral skeletal muscle relaxants. Am JHosp Pharm 1980; 37: 1313–23
290.
Koyama E, Chiba K, Tani M, et al. Reappraisal of human CYP450 isoforms involved in imipramine N-demethylation and 2-hydroxylation: a study using microsomes obtained from putative extensive and poor metabolizers of S-mephenytoin and eleven recombinant human CYP450s. J Pharmacol Exp Ther 1997; 281: 1199–210PubMed
291.
Venkatakrishnan K, Greenblatt DJ, von Moltke LL, et al. Five distinct human cytochromes mediate amitriptyline N-demethylation in vitro: dominance of CYP 2C19 and 3A4. J Clin Pharmacol 1998; 38: 112–21PubMed
292.
Nielsen KK, Flinois JP, Beaune PH, et al. The biotransformation of clomipramine in vitro, identification of the cytochrome P450s responsible for the separate metabolic pathways. J Pharmacol Exp Ther 1996; 277: 1659–64PubMed
293.
Spina E, Avenoso A, Campo GM, et al. Effect of ketoconazole on the pharmacokinetics of imipramine and desipramine in healthy subjects. Br J Clin Pharmacol 1997; 43: 315–8PubMedCrossRef
294.
Rochat B, Amey M, Gillet M, et al. Identification of three cytochrome P450 isozymes involved in N-demethylation of citalopram enantiomers in human liver microsomes. Pharma-cogenetics 1997; 7: 1–10
295.
Kobayashi K, Chiba K, Yagi T, et al. Identification of cytochrome P450 isoforms involved in citalopram N-demethylation by human liver microsomes. J Pharmacol Exp Ther 1997; 280: 927–33PubMed
296.
Madsen H, Rasmussen BB, Brosen K. Imipramine demethylation in vivo: impact of CYP1A2, CYP2C19, and CYP3A4. Clin Pharmacol Ther 1997; 61: 319–24PubMedCrossRef
297.
Madsen H, Hansen TS, Brosen K. Imipramine metabolism in relation to the sparteine oxidation polymorphism: a family study. Pharmacogenetics 1996; 6: 513–9PubMedCrossRef
298.
Koyama E, Tanaka T, Chiba K, et al. Steady-state plasma concentrations of imipramine and desipramine in relation to S-mephenytoin 4′-hydroxylation status in Japanese depressive patients. J Clin Psychopharmacol 1996; 16(4): 286–93PubMedCrossRef
299.
Morinobu S, Tanaka T, Kawakatsu S, et al. Effects of genetic defects in the CYP2C19 gene on the N-demethylation of imipramine, and clinical outcome of imipramine therapy. Psychiatry Clin Neurosci 1997; 51: 253–7PubMedCrossRef
300.
Glassman AH, Perel JM, Shostak M, et al. Clinical implications of imipramine plasma levels for depressive illness. Arch Gen Psychiatry 1977; 34: 197–204PubMedCrossRef
301.
Kantor SJ, Glassman AH, Bigger JTJ, et al. The cardiac effects of therapeutic plasma concentrations of imipramine. Am J Psychiatry 1978; 135: 534–8PubMed
302.
Spigset O, Hedenmalm K, Dahl ML, et al. Seizures and myoc-lonus associated with antidepressant treatment: assessment of potential risk factors, including CYP2D6 and CYP2C19 polymorphisms, and treatment with CYP2D6 inhibitors. Acta Psy-chiatrScand 1997; 96: 379–84CrossRef
303.
Balant-Gorgia AE, Balant LP, Andreoli A. Pharmacokinetic optimization of the treatment of psychosis. Clin Pharmacokinet 1993; 25: 217–36PubMedCrossRef
304.
Caccia S. Metabolism of the newer antidepressants: an overview of the pharmacological and pharmacokinetic implications. Clin Pharmacokinet 1998; 34: 281–302PubMedCrossRef
305.
Shin JG, Soukhova N, Flockhart DA. Effect of antipsychotic drugs on human liver cytochrome P-450 (CYP450) isoforms in vitro: preferential inhibition of CYP2D6. Drug Metab Dis-pos 1999; 27: 1078–84
306.
Meyer UA, Amrein R, Balant LP, et al. Antidepressants and drug-metabolizing enzymes: expert group report. Acta Psy-chiatrScand 1996; 93: 71–9CrossRef
307.
Alvan G, Bechtel P, Iselius L, et al. Hydroxylation polymorphisms of debrisoquine and mephenytoin in European populations. Eur J Clin Pharmacol 1990; 39: 533–7PubMedCrossRef
308.
Johansson I, Oscarson M, Yue QY, et al. Genetic analysis of the Chinese chromosome P4502D locus: characterization of variant CYP2D6 genes present in subjects with diminished capacity for debrisoquine hydroxylation. Mol Pharmacol 1994; 46: 452–9PubMed
309.
Yu KS, Yim DS, Cho JY, et al. Effect of omeprazole on the pharmacokinetics of moclobemide according to the genetic polymorphism of CYP2C19. Clin Pharmacol Ther 2001; 69: 266–73PubMedCrossRef
310.
Rosholm JU, Hallas J, Gram LF. Concurrent use of more than one major psychotropic drug (polypsychopharmacy) in outpatients: a prescription database study. Br J Clin Pharmacol 1994; 37: 533–8PubMedCrossRef
311.
Zimmer R, Gieschke R, Fischbach R, et al. Interaction studies with moclobemide. Acta Psychiatr Scand Suppl 1990; 360: 84–6PubMedCrossRef
312.
Perucca E, Richens A. Interaction between phenytoin and imipramine. Br J Clin Pharmacol 1977; 4: 485–6PubMedCrossRef
313.
Shapiro PA. Cimetidine-imipramine interaction: case report and comments [letter]. Am J Psychiatry 1984; 141: 152
314.
Henauer SA, Hollister LE. Cimetidine interaction with imipra-mine and nortriptyline. Clin Pharmacol Ther 1984; 35: 183–7PubMedCrossRef
315.
Curry SH, Devane CL, Wolfe MM. Cimetidine interaction with amitriptyline. Eur J Clin Pharmacol 1985; 29: 429–33PubMedCrossRef
316.
Schoerlin MP, Mayersohn M, Hoevels B, et al. Cimetidine alters the disposition kinetics of the monoamine oxidase-A inhibitor moclobemide. Clin Pharmacol Ther 1991; 49: 32–8PubMedCrossRef
317.
Conus P, Bondolfi G, Eap CB, et al. Pharmacokinetic flu-voxamine-clomipramine interaction with favorable therapeutic consequences in therapy-resistant depressive patient. Pharmacopsychiatry 1996; 29: 108–10PubMedCrossRef
318.
Szegedi A, Wetzel H, Leal M, et al. Combination treatment with clomipramine and fluvoxamine: drug monitoring, safety, and tolerability data. J Clin Psychiatry 1996; 57: 257–64PubMed
319.
Bondolfi G, Chautems C, Rochat B, et al. Non-response to citalopram in depressive patients: pharmacokinetic and clinical consequences of a fluvoxamine augmentation. Psycho-pharmacology (Berl) 1996; 128: 421–5CrossRef
320.
Leroi I, Walentynowicz MA. Fluoxetine-imipramine interaction [letter]. Can J Psychiatry 1996; 41: 318–9PubMed
321.
Bergstrom RF, Peyton AL, Lemberger L. Quantification and mechanism of the fluoxetine and tricyclic antidepressant interaction. Clin Pharmacol Ther 1992; 51: 239–48PubMedCrossRef
322.
Dingemanse J, Wallnofer A, Gieschke R, et al. Pharmacokinetic and pharmacodynamic interactions between fluoxetine and moclobemide in the investigation of development of the ’serotonin syndrome’. Clin Pharmacol Ther 1998; 63: 403–13PubMedCrossRef
323.
Preskorn SH, Baker B. Fatality associated with combined fluoxetine-amitriptyline therapy [letter]. JAMA 1997; 277: 1682PubMed
324.
Hewick DS, Sparks RG, Stevenson IH, et al. Induction of imip-ramine metabolism following barbiturate administration [abstract]. Br J Clin Pharmacol 1977; 4: 399PPubMedCrossRef
325.
Garey KW, Amsden GW, Johns CA. Possible interaction between imipramine and butalbital. Pharmacotherapy 1997; 17: 1041–2PubMed
326.
Schmider J, Greenblatt DJ, von Moltke LL, et al. N-Demethyl-ation of amitriptyline in vitro: role of cytochrome P-450 3A (CYP3A) isoforms and effect of metabolic inhibitors. J Pharmacol Exp Ther 1995; 275: 592–7PubMed
327.
Harvey AT, Preskorn SH. Cytochrome P450 enzymes: interpretation of their interactions with selective serotonin reuptake inhibitors. Part II. J Clin Psychopharmacol 1996; 16: 345–55PubMedCrossRef
328.
Taylor D. Selective serotonin reuptake inhibitors and tricyclic antidepressants in combination: interactions and therapeutic uses. Br J Psychiatry 1995; 167: 575–80PubMedCrossRef
329.
Kirchheiner J, Brosen K, Dahl ML, et al. CYP2D6 and CYP2C19 genotype-based dose recommendations for antidepressants: a first step towards subpopulation-specific dosages. Acta Psychiatr Scand 2001; 104: 173–92PubMedCrossRef
330.
Ward SA, Helsby NA, Skjelbo E, et al. The activation of the biguanide antimalarial proguanil co-segregates with mephenytoin oxidation polymorphism: a panel study. Br J Clin Pharmacol 1991; 31: 689–92PubMedCrossRef
331.
Caraco Y, Sheller J, Wood AJ. Pharmacogenetic determination of the effects of codeine and prediction of drug interactions. J Pharmacol Exp Ther 1996; 278: 1165–74PubMed
332.
Edstein MD, Yeo AE, Kyle DE, et al. Proguanil polymorphism does not affect the antimalarial activity of proguanil combined with atovaquone in vitro. Trans R Soc Trop Med Hyg 1996; 90: 418–21PubMedCrossRef
333.
Kaneko A, Bergqvist Y, Taleo G, et al. Proguanil disposition and toxicity in malaria patients from Vanuatu with high frequencies of CYP2C19 mutations. Pharmacogenetics 1999; 9: 317–26PubMedCrossRef
334.
Kortunay S, Basci NE, Bozkurt A, et al. The hydroxylation of omeprazole correlates with S-mephenytoin and proguanil metabolism. Eur J Clin Pharmacol 1997; 53: 261–4PubMedCrossRef
335.
Kaneko A, Bergqvist Y, Takechi M, et al. Intrinsic efficacy of proguanil against falciparum and vivax malaria independent of the metabolite cycloguanil. J Infect Dis 1999; 179: 974–9PubMedCrossRef
336.
Zhang KE, Wu E, Patick AK, et al. Circulating metabolites of the human immunodeficiency virus protease inhibitor nelfinavir in humans: structural identification, levels in plasma, and antiviral activities. Antimicrob Agents Chemo-ther 2001; 45: 1086–93CrossRef
337.
Baede-van Dijk PA, Hugen PW, Verweij-van Wissen CP, et al. Analysis of variation in plasma concentrations of nelfinavir and its active metabolite M8 in HIV-positive patients. AIDS 2001; 15: 991–8PubMedCrossRef
338.
Knodell RG, Hall SD, Wilkinson GR, et al. Hepatic metabolism of tolbutamide: characterization of the form of cytochrome P-450 involved in methyl hydroxylation and relationship to in vivo disposition. J Pharmacol Exp Ther 1987; 241: 1112–9PubMed
339.
Miners JO, Smith KJ, Robson RA, et al. Tolbutamide hydroxylation by human liver microsomes: kinetic characterization and relationship to other cytochrome P-450 dependent xenobiotic oxidations. Biochem Pharmacol 1988; 37: 1137–44PubMedCrossRef
340.
Desta Z, Soukhova N, Shin JG, et al. Involvement of cytochrome P450 2C19 in methylhydroxylation of tolbutamide in vitro [abstract]. Clin Pharmacol Ther 1999; 67: 167
341.
Wester MR, Lasker JM, Johnson EF, et al. CYP2C19 participates in tolbutamide hydroxylation by human liver microsomes. Drug Metab Dispos 2000; 28: 354–9PubMed
342.
Shon JH, Yoon YR, Kim KA, et al. Effects of CYP2C19 and CYP2C9 genetic polymorphisms on the disposition of and blood glucose lowering response to tolbutamide in humans. Pharmacogenetics 2002; 12: 111–9PubMedCrossRef
343.
Inoue K, Yamazaki H, Imiya K, et al. Relationship between CYP2C9 and 2C19 genotypes and tolbutamide methyl hydroxylation and S-mephenytoin 4′-hydroxylation activities in livers of Japanese and Caucasian populations. Pharmacogenetics 1997; 7: 103–13PubMedCrossRef
344.
Xie HG, Xu ZH, Huang SL, et al. No correlation between side-chain of propranolol oxidation and S-mephenytoin 4′-hy-droxylase activity. Zhongguo Yao Li Xue Bao 1997; 18: 216–8PubMed
345.
Ford GA, Wood SM, Daly AK. CYP2D6 and CYP2C19 genotypes of patients with terodiline cardiotoxicity identified through the yellow card system. Br J Clin Pharmacol 2000; 50: 77–80PubMedCrossRef
346.
347.
Kaisary A, Smith P, Jaczq E, et al. Genetic predisposition to bladder cancer: ability to hydroxylate debrisoquine and mephenytoin as risk factors. Cancer Res 1987; 47: 5488–93PubMed
348.
Benhamou S, Bouchardy C, Dayer P. Lung cancer risk in relation to mephenytoin hydroxylation activity. Pharmacogenetics 1997; 7: 157–9PubMedCrossRef
349.
Tsuneoka Y, Fukushima K, Matsuo Y, et al. Genotype analysis of the CYP2C19 gene in the Japanese population. Life Sci 1996; 59: 1711–5PubMedCrossRef
350.
Brockmoller J, Cascorbi I, Kerb R, et al. Combined analysis of inherited polymorphisms in arylamine N-acetyltransferase 2, glutathione S-transferases Ml and Tl, microsomal epoxide hydrolase, and cytochrome P450 enzymes as modulators of bladder cancer risk. Cancer Res 1996; 56: 3915–25PubMed
351.
Roddam PL, Rollinson S, Kane E, et al. Poor metabolizers at the cytochrome P450 2D6 and 2C19 loci are at increased risk of developing adult acute leukemia. Pharmacogenetics 2000; 10: 605–15PubMedCrossRef
352.
Chau TK, Marakami S, Kawai B, et al. Genotype analysis of the CYP2C19 gene in HCV-seropositive patients with cirrhosis and hepatocellular carcinoma. Life Sci 2000; 67: 1719–24PubMedCrossRef
353.
Horsmans Y, Lannfelt L, Pessayre D, et al. Possible association between poor metabolism of mephenytoin and hepatotoxicity caused by Atrium, a fixed combination preparation containing phenobarbital, febarbamate and difebarbamate. J Hepatol 1994; 21: 1075–9PubMedCrossRef
354.
May DG, Black CM, Olsen NJ, et al. Scleroderma is associated with differences in individual routes of drug metabolism: a study with dapsone, debrisoquin, and mephenytoin. Clin Pharmacol Ther 1990; 48: 286–95PubMedCrossRef
355.
Helsby NA, Ward SA, Parslew RA, et al. Hepatic cytochrome P450 CYP2C activity in psoriasis: studies using proguanil as a probe compound. Acta Derm Venereol 1998; 78: 81–3PubMedCrossRef
356.
Britto MR, McKean HE, Bruckner GG, et al. Polymorphisms in oxidative drug metabolism: relationship to food preference. Br J Clin Pharmacol 1991; 32: 235–7PubMedCrossRef
Metadata
Title
Clinical Significance of the Cytochrome P450 2C19 Genetic Polymorphism
Authors
Zeruesenay Desta
Xiaojiong Zhao
Jae-Gook Shin
Dr David A. Flockhart
Publication date
01-10-2002
Publisher
Springer International Publishing
Published in
Clinical Pharmacokinetics / Issue 12/2002
Print ISSN: 0312-5963
Electronic ISSN: 1179-1926
DOI
https://doi.org/10.2165/00003088-200241120-00002