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Clinical Pharmacokinetics
Published in: Clinical Pharmacokinetics 3/2010

01-03-2010 | Original Research Article

A Semi-Mechanistic Model to Predict the Effects of Liver Cirrhosis on Drug Clearance

Authors: Dr Trevor N. Johnson, Koen Boussery, Karen Rowland-Yeo, Geoffrey T. Tucker, Amin Rostami-Hodjegan

Published in: Clinical Pharmacokinetics | Issue 3/2010

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Abstract

Background and Objective: Liver cirrhosis is characterized by a decrease in functional hepatocytes, lowered circulating levels of plasma proteins and alterations in blood flow due to the development of portacaval shunts. Depending on the interplay between these parameters and the characteristics of an administered drug, varying degrees of impaired systemic clearance and first-pass metabolism are anticipated. The Simcyp Population-based ADME Simulator has already been used successfully to incorporate genetic, physiological and demographic attributes of certain subgroups within healthy populations into in vitro-in vivo extrapolation (IVIVE) of xenobiotic clearance. The objective of this study was to extend population models to predict systemic and oral drug clearance in relation to the severity of liver cirrhosis.
Methods: Information on demographics, changes in hepatic blood flow, cytochrome P450 enzymes, liver size, plasma protein binding and renal function was incorporated into three separate population libraries. The latter corresponded to Child-Pugh were used to predict tscores A (mild), B (moderate) and C (severe) liver cirrhosis. These libraries, together with mechanistic IVIVE within the Simcyp Simulator, he clearance of intravenous and oral midazolam, oral caffeine, intravenous and oral theophylline, intravenous and oral metoprolol, oral nifedipine, oral quinidine, oral diclofenac, oral sildenafil, and intravenous and oral omeprazole. The simulated patients matched the clinical studies as closely as possible with regard to demographics and Child-Pugh scores. Predicted clearance values in both healthy control and liver cirrhosis populations were compared with observed values, as were the fold increases in clearance values between these populations.
Results: There was good agreement (lack of statistically significant difference, two-tailed paired t-test) between observed and predicted clearance ratios, with the exception of those for two studies of intravenous omeprazole. Predicted clearance ratios were within 0.8- to 1.25-fold of observed ratios in 65% of cases (range 0.34- to 2.5-fold).
Conclusion: The various drugs that were studied showed different changes in clearance in relation to disease severity, and a ‘one size fits all’ solution does not exist without considering the multiple sources of the changes. Predictions of the effects of liver cirrhosis on drug clearance are of potential value in the design of clinical studies during drug development and, clinically, in the assessment of likely dosage adjustment.
Literature
1.
Rodighiero V. Effects of liver disease on pharmacokinetics: an update. Clin Pharmacokinet 1999 Nov; 37(5): 399–431PubMedCrossRef
2.
Johnson TN, Thomson AH. Pharmacokinetics of drugs in liver disease. In: North-Lewis P, editor. Drugs in liver disease. London: Pharmaceutical Press, 2008
3.
Hasselstrom J, Eriksson S, Persson A, et al. The metabolism and bioavailability of morphine in patients with severe liver cirrhosis. Br J Clin Pharmacol 1990 Mar; 29(3): 289–97PubMedCrossRef
4.
5.
6.
Reidenberg MM. Drugs in liver disease [comment]. Clin Pharmacol Ther 1998; 64(4): 465CrossRef
7.
Edginton AN, Willmann S. Physiology-based simulations of a pathological condition: prediction of pharmacokinetics in patients with liver cirrhosis. Clin Pharmacokinet 2008; 47(11): 743–52PubMedCrossRef
8.
Jamei M, Dickinson GL, Rostami-Hodjegan A. A framework for assessing inter-individual variability in pharmacokinetics using virtual human populations and integrating general knowledge of physical chemistry, biology, anatomy, physiology and genetics: a tale of ‘bottom-up’ vs ‘top-down’ recognition of covariates. Drug Metab Pharmacokinet 2009; 24(1): 53–75PubMedCrossRef
9.
Jamei M, Marciniak S, Feng K, et al. The Simcyp® Population-based ADME Simulator. Expert Opin Drug Metab Toxicol 2009 Feb; 5(2): 211–23PubMedCrossRef
10.
Rostami-Hodjegan A, Tucker GT. Simulation and prediction of in vivo drug metabolism in human populations from in vitro data. Nature Rev Drug Discov 2007 Feb; 6(2): 140–8CrossRef
11.
Howgate EM, Rowland Yeo K, Proctor NJ, et al. Prediction of in vivo drug clearance from in vitro data: I. Impact of inter-individual variability. Xenobiotica 2006 Jun; 36(6): 473–97
12.
Proctor NJ, Tucker GT, Rostami-Hodjegan A. Predicting drug clearance from recombinantly expressed CYPs: intersystem extrapolation factors. Xenobiotica 2004 Feb; 34(2): 151–78PubMedCrossRef
13.
Wilkinson GR, Shand DG. Commentary: a physiological approach to hepatic drug clearance. Clin Pharmacol Ther 1975 Oct; 18(4): 377–90PubMed
14.
Rostami-Hodjegan A, Tucker GT. In silico simulations to assess the in vivo consequences of in vitro metabolic drug-drug interactions. Drug Discovery Today: Technologies 2004; 1: 441–8CrossRef
15.
Johnson TN, Rostami-Hodjegan A, Tucker GT. Predictionofthe clearance of eleven drugs and associated variabilityinneonates, infants and children. Clin Pharmacokinet 2006; 45(9): 931–56PubMedCrossRef
16.
Yang J, Jamei M, Yeo KR, et al. Prediction of intestinal first-pass drug metabolism. Curr Drug Metab 2007 Oct; 8(7): 676–84PubMedCrossRef
17.
Paine MF, Hart HL, Ludington SS, et al. The human intestinal cytochrome P450 “pie”. Drug Metab Dispos 2006 May; 34(5): 880–6PubMedCrossRef
18.
Sun D, Lennernas H, Welage LS, et al. Comparison of human duodenum and Caco-2 gene expression profiles for 12,000 gene sequences tags and correlation with permeability of 26 drugs. Pharm Res 2002 Oct; 19(10): 1400–16PubMedCrossRef
19.
Inoue S, Howgate EM, Rowland-Yeo K, et al. Prediction of in vivo drug clearance from in vitro data: II: Potential inter-ethnic differences. Xenobiotica 2006 Jun; 36(6): 499–513PubMedCrossRef
20.
Johnson TN, Tucker GT, Tanner MS, et al. Changes in liver volume from birth to adulthood: ameta-analysis. Liver Transpl 2005 Dec; 11(12): 1481–93PubMedCrossRef
21.
Rowland-Yeo K, Rostami-Hodjegan A, Tucker GT. Abundance of cyto-chromes P450inhuman liver:ameta-analysis [abstract]. Br J Clin Pharmacol 2004; 57(5): 687
22.
Barter ZE, Bayliss MK, Beaune PH, et al. Scaling factors for the extrapolation of in vivo metabolic drug clearance from in vitro data: reaching a consensus on values of human microsomal protein and hepatocellularity per gram of liver. Curr Drug Metab 2007 Jan; 8(1): 33–45PubMedCrossRef
23.
Klotz U. Antiarrhythmics: elimination and dosage considerations in hepatic impairment. Clin Pharmacokinet 2007; 46(12): 985–96PubMedCrossRef
24.
Andersen V, Pedersen N, Larsen NE, et al. Intestinal first pass metabolism of midazolam in liver cirrhosis: effect of grapefruit juice. Br J Clin Pharmacol 2002 Aug; 54(2): 120–4PubMedCrossRef
25.
Orlando R, Piccoli P, De Martin S, et al. Cytochrome P450 1A2 is a major determinant of lidocaine metabolism in vivo: effects of liver function. Clin Pharmacol Ther 2004 Jan; 75(1): 80–8PubMedCrossRef
26.
Pique JM, Feu F, de Prada G, et al. Pharmacokinetics of omeprazole given by continuous intravenous infusion to patients with varying degrees of hepatic dysfunction. Clin Pharmacokinet 2002; 41(12): 999–1004PubMedCrossRef
27.
Pugh RN, Murray-Lyon IM, Dawson JL, et al. Transectionofthe oesophagus for bleeding oesophageal varices. Br J Surg 1973 Aug; 60(8): 646–9PubMedCrossRef
28.
Leon DA, McCambridge J. Liver cirrhosis mortality rates in Britain from 1950 to 2002: an analysis of routine data. Lancet 2006 Jan 7; 367(9504): 52–6PubMedCrossRef
29.
Garello E, Battista S, Bar F, et al. Evaluation of hepatic function in liver cirrhosis: clinical utility of galactose elimination capacity, hepatic clearance of D-sorbitol, and laboratory investigations. Digest Dis Sci 1999 Apr; 44(4): 782–8PubMedCrossRef
30.
Kwon AH, Matsui Y, Ha-Kawa SK, et al. Functional hepatic volume measured by technetium-99m-galactosyl-human serum albumin liver scintigraphy: comparison between hepatocyte volume and liver volume by computed tomography. Am J Gastroenterol 2001 Feb; 96(2): 541–6PubMedCrossRef
31.
Li YM, Lv F, Xu X, et al. Evaluation of liver functional reserve by combining D-sorbitol clearance rate and CT measured liver volume. World J Gastroenterol 2003 Sep; 9(9): 2092–5PubMed
32.
Lin XZ, Sun YN, Liu YH, et al. Liver volume in patients with or without chronic liver diseases. Hepatogastroenterology 1998 Jul-Aug; 45(22): 1069–74PubMed
33.
Miki K, Kubota K, Inoue Y, et al. Receptor measurements via Tc-GSA kinetic modeling are proportional to functional hepatocellular mass. J Nucl Med 2001 May; 42(5): 733–7PubMed
34.
Matsui Y, Tu W, Kitade H, et al. Hepatocyte volume as an indicator of hepatic functional reserve in cirrhotic patients with liver tumours. J Gastroenterol Hepatol 1996 Jun; 11(6): 540–5PubMedCrossRef
35.
Guengerich FP, Turvy CG. Comparison of levels of several human microsomal cytochrome P-450 enzymes and epoxide hydrolase in normal and disease states using immunochemical analysis of surgical liver samples. J Pharmacol Exp Ther 1991 Mar; 256(3): 1189–94PubMed
36.
George J, Murray M, Byth K, et al. Differential alterations of cytochrome P450 proteins in livers from patients with severe chronic liver disease. Hepatology 1995 Jan; 21(1): 120–8PubMed
37.
George J, Liddle C, Murray M, et al. Pre-translational regulation of cytochrome P450 genes is responsible for disease-specific changes of individual P450 enzymes among patients with cirrhosis. Biochem Pharmacol 1995 Mar 30; 49(7): 873–81PubMedCrossRef
38.
Frye RF, Zgheib NK, Matzke GR, et al. Liver disease selectively modulates cytochrome P450-mediated metabolism. Clin Pharmacol Ther 2006 Sep; 80(3): 235–45PubMedCrossRef
39.
Sotaniemi EA, Rautio A, Backstrom M, et al. CYP3A4 and CYP2A6 activities marked by the metabolism of lignocaine and coumarin in patients with liver and kidney diseases and epileptic patients. Br J Clin Pharmacol 1995 Jan; 39(1): 71–6PubMedCrossRef
40.
Woodhouse KW, Mitchison HC, Mutch E, et al. The metabolism of 7-ethoxycoumarin in human liver microsomes and the effect of primary biliary cirrhosis: implications for studies of drug metabolism in liver disease. Br J Clin Pharmacol 1985 Jul; 20(1): 77–80PubMedCrossRef
41.
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 Jul; 64(1): 8–17PubMedCrossRef
42.
Ohnishi A, Murakami S, Akizuki S, et al. In vivo metabolic activity of CYP2C19 and CYP3A in relation to CYP2C19 genetic polymorphism in chronic liver disease. J Clin Pharmacol 2005 Nov; 45(11): 1221–9PubMedCrossRef
43.
Chalon SA, Desager JP, Desante KA, et al. Effect of hepatic impairment on the pharmacokinetics of atomoxetine and its metabolites. Clin Pharmacol Ther 2003 Mar; 73(3): 178–91PubMedCrossRef
44.
Yang LQ, Li SJ, Cao YF, et al. Different alterations of cytochrome P450 3A4 isoform and its gene expression in livers of patients with chronic liver diseases. World J Gastroenterol 2003 Feb; 9(2): 359–63PubMed
45.
Moffat AC, Osselton MD, Widdop B, editors. Clarke’s analysis of drugs and poisons. London: Pharmaceutical Press, 2004
46.
Rostami-Hodjegan A, Kroemer HK, Tucker GT. In-vivo indices of enzyme activity: the effect of renal impairment on the assessment of CYP2D6 activity. Pharmacogenetics 1999 Jun; 9(3): 277–86PubMedCrossRef
47.
Alberino F, Gatta A, Amodio P, et al. Nutrition and survival in patients with liver cirrhosis. Nutrition 2001 Jun; 17(6): 445–50PubMedCrossRef
48.
Roongpisuthipong C, Sobhonslidsuk A, Nantiruj K, et al. Nutritional assessment in various stages of liver cirrhosis. Nutrition 2001 Sep; 17(9): 761–5PubMedCrossRef
49.
Tessari P, Barazzoni R, Kiwanuka E, et al. Impairment of albumin and whole body postprandial protein synthesis in compensated liver cirrhosis. Am J Physiol 2002 Feb; 282(2): E304–11
50.
Viani A, Rizzo G, Carrai M, et al. Interindividual variability in the concentrations of albumin and alpha-1-acid glycoprotein in patients with renal or liver disease, newborns and healthy subjects: implications for binding of drugs. Int J Clin Pharmacol Ther Toxicol 1992 Apr; 30(4): 128–33PubMed
51.
Barry M, Keeling PW, Weir D, et al. Severity of cirrhosis and the relationship of alpha 1-acid glycoprotein concentration to plasma protein binding of lidocaine. Clin Pharmacol Ther 1990 Mar; 47(3): 366–70PubMedCrossRef
52.
Verbeeck RK. Pharmacokinetics and dosage adjustment in patients with hepatic dysfunction. Eur J Clin Pharmacol 2008 Dec; 64(12): 1147–61PubMedCrossRef
53.
Boker KHW, Franzen A, Wrobel M, et al. Regulation of hepatic blood flow in patients with liver cirrhosis and after liver transplantation. Pathophysiol 2000; 6: 251–60CrossRef
54.
Liu TT, Wong WJ, Hou MC, et al. Hemorheology in patients with liver cirrhosis: special emphasis on its relation to severity of esophageal variceal bleeding. J Gastroen Hepatol 2006 May; 21(5): 908–13CrossRef
55.
Wong F, Girgrah N, Graba J, et al. The cardiac response to exercise in cirrhosis. Gut 2001 Aug; 49(2): 268–75PubMedCrossRef
56.
Kontos HA, Shapiro W, Mauck HP, et al. General and regional circulatory alterations in cirrhosis of the liver. Am J Med 1964 Oct; 37: 526–35PubMedCrossRef
57.
Murray JF, Dawson AM, Sherlock S. Circulatory changes in chronic liver disease. Am J Med 1958 Mar; 24(3): 358–67PubMedCrossRef
58.
Andersen UB, Moller S, Bendtsen F, et al. Cardiac output determined by echocardiography in patients with cirrhosis: comparison with the indicator dilution technique. Eur J Gastroen Hepat 2003 May; 15(5): 503–7
59.
Dincer D, Besisk F, Demirkol O, et al. Relationships between hemodynamic alterations and Child-Pugh score in patients with cirrhosis. Hepatogastroenterology 2005 Sep-Oct; 52(65): 1521–5PubMed
60.
Iwao T, Oho K, Sakai T, et al. Splanchnic and extrasplanchnic arterial hemodynamics in patients with cirrhosis. J Hepatol 1997 Nov; 27(5): 817–23PubMedCrossRef
61.
Jalan R, Forrest EH, Redhead DN, et al. Reduction in renal blood flow following acute increase in the portal pressure: evidence for the existence of a hepatorenal reflex in man? Gut 1997 May; 40(5): 664–70PubMed
62.
Henriksen JH, Bendtsen F, Moller S. Normal red cell cardiac output in the hyperkinetic syndrome of alcoholic cirrhosis. J Hepatol 2001 May; 34(5): 782–3PubMedCrossRef
63.
Annet L, Materne R, Danse E, et al. Hepatic flow parameters measured with MR imaging and Doppler US: correlations with degree of cirrhosis and portal hypertension. Radiology 2003 Nov; 229(2): 409–14PubMedCrossRef
64.
Kayacetin E, Efe D, Dogan C. Portal and splenic hemodynamics in cirrhotic patients: relationship between esophageal variceal bleeding and the severity of hepatic failure. J Gastroenterol 2004 Jul; 39(7): 661–7PubMedCrossRef
65.
Moreno AH, Burchell AR, Rousselot LM, et al. Portal blood flow in cirrhosis of the liver. J Clin Invest 1967 Mar; 46(3): 436–45PubMedCrossRef
66.
Tsushima Y, Blomley JK, Kusano S, et al. The portal component of hepatic perfusion measured by dynamic CT: an indicator of hepatic parenchymal damage. Dig Dis Sci 1999 Aug; 44(8): 1632–8PubMedCrossRef
67.
Van Beers BE, Leconte I, Materne R, et al. Hepatic perfusion parameters in chronic liver disease: dynamic CT measurements correlated with disease severity. Am J Roentgenol 2001 Mar; 176(3): 667–73
68.
Iwao T, Toyonaga A, Shigemori H, et al. Hepatic artery hemodynamic responsiveness to altered portal blood flow in normal and cirrhotic livers. Radiology 1996 Sep; 200(3): 793–8PubMed
69.
Ohnishi K, Saito M, Nakayama T, et al. Portal venous hemodynamics in chronic liver disease: effects of posture change and exercise. Radiology 1985 Jun; 155(3): 757–61PubMed
70.
Pan Z, Wu XJ, Li JS, et al. Functional hepatic flow in patients with liver cirrhosis. World J Gastroenterol 2004 Mar 15; 10(6): 915–8PubMed
71.
Sudhamshu KC, Matsutani S, Maruyama H, et al. Doppler study of hepatic vein in cirrhotic patients: correlation with liver dysfunction and hepatic hemodynamics. World J Gastroenterol 2006 Sep 28; 12(36): 5853–8PubMed
72.
Bolognesi M, Sacerdoti D, Bombonato G, et al. Change in portal flow after liver transplantation: effect on hepatic arterial resistance indices and role of spleen size. Hepatology 2002 Mar; 35(3): 601–8PubMedCrossRef
73.
Henderson JM, Mackay GJ, Kutner MH, et al. Volumetric and functional liver blood flow are both increased in the human transplanted liver. J Hepatol 1993 Feb; 17(2): 204–7PubMedCrossRef
74.
Sukigara M, Iwatsuki S, Stieber A, et al. Changes of portal venous flow velocity after liver transplantation and its causes. Transplant Proc 1994 Aug; 26(4): 2261–2PubMed
75.
Hamato N, Moriyasu F, Someda H, et al. Distribution of mesenteric and splenic blood flow in cirrhosis of the liver as estimated by radionuclide angiography. Intern Med 1993 Jun; 32(6): 445–8PubMedCrossRef
76.
Kashiwagi T, Fukui H, Kozuka T, et al. Assessment of portosystemic shunting from superior mesenteric vein by duodenal administration of iodoamphetamine I123. Eur J Nucl Med 1992; 19(3): 181–5PubMedCrossRef
77.
Kashiwagi T, Azuma M, Ikawa T, et al. Portosystemic shunting in portal hypertension: evaluation with portal scintigraphy with transrectally administered I-123 IMP. Radiology 1988 Oct; 169(1): 137–40PubMed
78.
Chalasani N, Gorski JC, Patel NH, et al. Hepatic and intestinal cytochrome P450 3A activity in cirrhosis: effects of transjugular intrahepatic portosystemic shunts. Hepatology 2001 Dec; 34(6): 1103–8PubMedCrossRef
79.
McConn II DJ, Lin YS, Mathisen TL, et al. Reduced duodenal cytochrome P450 3A protein expression and catalytic activity in patients with cirrhosis. Clin Pharmacol Ther 2009 Apr; 85(4): 387–93PubMedCrossRef
80.
Woitas RP, Flommersfeld S, Stoffel-Wagner B, et al. Renal functional reserve is well maintainedin patients with advanced liver cirrhosis and ascites. Scand J Gastroenterol 2002 Nov; 37(11): 1321–7PubMedCrossRef
81.
Wong F, Blendis L. New challenge of hepatorenal syndrome: prevention and treatment. Hepatology 2001 Dec; 34(6): 1242–51PubMedCrossRef
82.
Arieff AI, Chidsey CA. Renal function in cirrhosis and the effects of prostaglandin A. Am J Med 1974 May; 56(5): 695–703PubMedCrossRef
83.
DeSanto NG, Anastasio P, Loguercio C, et al. Creatinine clearance: an inadequate marker of renal filtration in patients with early posthepatitic cirrhosis (Child A) without fluid retention and muscle wasting. Nephron 1995; 70(4): 421–4PubMedCrossRef
84.
Laffi G, Pinzani M, Meacci E, et al. Renal hemodynamic and natriuretic effects of human atrial natriuretic factor infusion in cirrhosis with ascites. Gastroenterology 1989 Jan; 96(1): 167–77PubMed
85.
Orlando R, Mussap M, Plebani M, et al. Diagnostic value of plasma cystatin C as a glomerular filtration marker in decompensated liver cirrhosis. Clin Chem 2002 Jun; 48(6 Pt 1): 850–8PubMed
86.
Pirlich M, Selberg O, Boker K, et al. The creatinine approach toestimateskeletal muscle mass in patients with cirrhosis. Hepatology 1996 Dec; 24(6): 1422–7PubMedCrossRef
87.
Roy L, Legault L, Pomier-Layrargues G. Glomerular filtration rate measurement in cirrhotic patients with renal failure. Clinical Nephrol 1998 Dec; 50(6): 342–6
88.
Skluzacek PA, Szewc RG, Nolan III CR, et al. Prediction of GFR in liver transplant candidates. Am J Kidney Dis 2003 Dec; 42(6): 1169–76PubMedCrossRef
89.
Woitas RP, Heller J, Stoffel-Wagner B, et al. Renal functional reserve and nitric oxide in patients with compensated liver cirrhosis. Hepatology 1997 Oct; 26(4): 858–64PubMedCrossRef
90.
Woitas RP, Stoffel-Wagner B, Flommersfeld S, et al. Correlation of serum concentrations of cystatin C and creatinine to inulin clearance in liver cirrhosis. Clin Chem 2000 May; 46(5): 712–5PubMed
91.
Park GJ, Katelaris PH, Jones DB, et al. Validity of the 13C-caffeine breath test as a noninvasive, quantitative test of liver function. Hepatology 2003 Nov; 38(5): 1227–36PubMedCrossRef
92.
Lewis FW, Rector Jr WG. Caffeine clearance in cirrhosis: the value of simplified determinations of liver metabolic capacity. J Hepatol 1992 Mar; 14(2–3): 157–62PubMedCrossRef
93.
Desmond PV, Patwardhan RV, Johnson RF, et al. Impaired elimination of caffeine in cirrhosis. Dig Dis Sci 1980 Mar; 25(3): 193–7PubMedCrossRef
94.
Scott NR, Stambuk D, Chakraborty J, et al. The pharmacokinetics ofcaffeine and its dimethylxanthine metabolites in patients with chronic liver disease. Br J Clin Pharmacol 1989 Feb; 27(2): 205–13PubMedCrossRef
95.
Lill JS, O’sullivan T, Bauer LA, et al. Pharmacokinetics of diclofenac sodium in chronic active hepatitis and alcoholic cirrhosis. J Clin Pharmacol 2000 Mar; 40(3): 250–7PubMedCrossRef
96.
Regardh CG, Jordo L, Ervik M, et al. Pharmacokinetics of metoprolol in patients with hepatic cirrhosis. Clin Pharmacokinet 1981 Sep–Oct; 6(5): 375–88PubMedCrossRef
97.
Pentikainen PJ, Valisalmi L, Himberg JJ, et al. Pharmacokinetics of midazolam following intravenous and oral administration in patients with chronic liver disease and in healthy subjects. J Clin Pharmacol 1989 Mar; 29(3): 272–7PubMed
98.
MacGilchrist AJ, Birnie GG, Cook A, et al. Pharmacokinetics and pharma-codynamics of intravenous midazolam in patients with severe alcoholic cirrhosis. Gut 1986 Feb; 27(2): 190–5PubMedCrossRef
99.
Ene MD, Roberts CJ. Pharmacokinetics of nifedipine after oral administration in chronic liver disease. J Clin Pharmacol 1987 Dec; 27(12): 1001–4PubMed
100.
Andersson T, Olsson R, Regardh CG, et al. Pharmacokinetics of [14C]omeprazole in patients with liver cirrhosis. Clin Pharmacokinet 1993 Jan; 24(1): 71–8PubMedCrossRef
101.
Rinetti M, Regazzi MB, Villani P, et al. Pharmacokinetics of omeprazole in cirrhotic patients. Arzneimittelforschung 1991 Apr; 41(4): 420–2PubMed
102.
Kumar R, Chawla YK, Garg SK, et al. Pharmacokinetics of omeprazole in patients with liver cirrhosis and extrahepatic portal venous obstruction. Methods Find Exp Clin Pharmacol 2003 Oct; 25(8): 625–30PubMedCrossRef
103.
Kessler KM, Humphries Jr WC, Black M, et al. Quinidine pharmacokinetics in patients with cirrhosis or receiving propranolol. Am Heart J 1978 Nov; 96(5): 627–35PubMedCrossRef
104.
Muirhead GJ, Wilner K, Colburn W, et al. The effects of age and renal and hepatic impairment on the pharmacokinetics of sildenafil. Br J Clin Pharmacol 2002; 53 Suppl. 1: 21–30SCrossRef
105.
Kraan J, Jonkman JH, Koeter GH, et al. The pharmacokinetics of theophylline and enprofylline in patients with liver cirrhosis and in patients with chronic renal disease. Eur J Clin Pharmacol 1988; 35(4): 357–62PubMedCrossRef
106.
Amodio P, Lauro S, Rondana M, et al. Theophylline pharmacokinetics and liver function indexes in chronic liver disease. Respiration 1991; 58(2): 106–11PubMedCrossRef
107.
Cukier A, Strauss E, Terra Filho M, et al. Theophylline metabolism in patients with hepatosplenic mansoniasis and cirrhosis. J Hepatol 1992 May; 15(1–2): 35–9PubMedCrossRef
108.
Lind T, Andersson T, Skanberg I, et al. Biliary excretion of intravenous [14C] omeprazole in humans. Clin Pharmacol Ther 1987 Nov; 42(5): 504–8PubMedCrossRef
109.
Virgolini I, Muller C, Angelberger P, et al. Functional liver imaging with 99Tcm-galactosyl-neoglycoalbumin (NGA) in alcoholic liver cirrhosis and liver fibrosis. Nucl Med Comm 1991 Jun; 12(6): 507–17CrossRef
110.
Pentikainen PJ, Neuvonen PJ, Jostell KG. Pharmacokinetics of chlormethiazole inhealthy volunteers and patients with cirrhosis of the liver. Eur J Clin Pharmacol 1980 Apr; 17(4): 275–84PubMedCrossRef
111.
Le Couteur DG, Fraser R, Hilmer S, et al. The hepatic sinusoid in aging and cirrhosis: effects on hepatic substrate disposition and drug clearance. Clin Pharmacokinet 2005; 44(2): 187–200PubMedCrossRef
112.
McLean AJ, Morgan DJ. Clinical pharmacokinetics in patients with liver disease. Clin Pharmacokinet 1991 Jul; 21(1): 42–69PubMedCrossRef
113.
Congiu M, Mashford ML, Slavin JL, et al. UDP glucuronosyltransferase mRNA levels in human liver disease. Drug Metab Dispos 2002 Feb; 30(2): 129–34PubMedCrossRef
114.
Furlan V, Demirdjian S, Bourdon O, et al. Glucuronidation of drugs by hepatic microsomes derived from healthy and cirrhotic human livers. J Pharmacol Exp Ther 1999 May; 289(2): 1169–75PubMed
Metadata
Title
A Semi-Mechanistic Model to Predict the Effects of Liver Cirrhosis on Drug Clearance
Authors
Dr Trevor N. Johnson
Koen Boussery
Karen Rowland-Yeo
Geoffrey T. Tucker
Amin Rostami-Hodjegan
Publication date
01-03-2010
Publisher
Springer International Publishing
Published in
Clinical Pharmacokinetics / Issue 3/2010
Print ISSN: 0312-5963
Electronic ISSN: 1179-1926
DOI
https://doi.org/10.2165/11318160-000000000-00000