Abstract
ATP-binding cassette (ABC) drug efflux transporters limit intracellular concentration of their substrates by pumping them out of cell through an active, energy dependent mechanism. Several of these proteins have been originally associated with the phenomenon of multidrug resistance; however, later on, they have also been shown to control body disposition of their substrates. P-glycoprotein (Pgp) is the first detected and the best characterized of ABC drug efflux transporters. Apart from tumor cells, its constitutive expression has been reported in a variety of other tissues, such as the intestine, brain, liver, placenta, kidney, and others. Being located on the apical site of the plasma membrane, Pgp can remove a variety of structurally unrelated compounds, including clinically relevant drugs, their metabolites, and conjugates from cells. Driven by energy from ATP, it affects many pharmacokinetic events such as intestinal absorption, brain penetration, transplacental passage, and hepatobiliary excretion of drugs and their metabolites. It is widely believed that Pgp, together with other ABC drug efflux transporters, plays a crucial role in the host detoxication and protection against xenobiotic substances. On the other hand, the presence of these transporters in normal tissues may prevent pharmacotherapeutic agents from reaching their site of action, thus limiting their therapeutic potential. This chapter focuses on P-glycoprotein, its expression, localization, and function in nontumor tissues and the pharmacological consequences hereof.
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References
Juliano RL, Ling V (1976) A surface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutants. Biochim Biophys Acta 455:152–162
Bosch I, Croop J (1996) P-glycoprotein multidrug resistance and cancer. Biochim Biophys Acta 1288:F37–F54
Goldstein LJ, Gottesman MM, Pastan I (1991) Expression of the MDR1 gene in human cancers. Cancer Treat Res 57:101–119
Kartner N, Riordan JR, Ling V (1983) Cell surface P-glycoprotein associated with multidrug resistance in mammalian cell lines. Science 221:1285–1288
Schinkel AH, Jonker JW (2003) Mammalian drug efflux transporters of the ATP binding cassette (ABC) family: an overview. Adv Drug Deliv Rev 55:3–29
Thiebaut F, Tsuruo T, Hamada H et al (1987) Cellular localization of the multidrug-resistance gene product P-glycoprotein in normal human tissues. Proc Natl Acad Sci USA 84:7735–7738
Fromm MF (2004) Importance of P-glycoprotein at blood–tissue barriers. Trends Pharmacol Sci 25:423–429
Seelig A, Landwojtowicz E (2000) Structure-activity relationship of P-glycoprotein substrates and modifiers. Eur J Pharm Sci 12:31–40
Benet LZ, Cummins CL (2001) The drug efflux-metabolism alliance: biochemical aspects. Adv Drug Deliv Rev 50(Suppl 1):S3–S11
Krishna R, Mayer LD (2000) Multidrug resistance (MDR) in cancer. Mechanisms, reversal using modulators of MDR and the role of MDR modulators in influencing the pharmacokinetics of anticancer drugs. Eur J Pharm Sci 11:265–283
Breedveld P, Beijnen JH, Schellens JH (2006) Use of P-glycoprotein and BCRP inhibitors to improve oral bioavailability and CNS penetration of anticancer drugs. Trends Pharmacol Sci 27:17–24
Ceckova-Novotna M, Pavek P, Staud F (2006) P-glycoprotein in the placenta: expression, localization, regulation and function. Reprod Toxicol 22:400–410
Lin JH (2003) Drug–drug interaction mediated by inhibition and induction of P-glycoprotein. Adv Drug Deliv Rev 55:53–81
Chen CJ, Clark D, Ueda K et al (1990) Genomic organization of the human multidrug resistance (MDR1) gene and origin of P-glycoproteins. J Biol Chem 265:506–514
Choudhuri S, Klaassen CD (2006) Structure, function, expression, genomic organization, and single nucleotide polymorphisms of human ABCB1 (MDR1), ABCC (MRP), and ABCG2 (BCRP) efflux transporters. Int J Toxicol 25:231–259
Callaghan R, Crowley E, Potter S, Kerr ID (2008) P-glycoprotein: so many ways to turn it on. J Clin Pharmacol 48:365–378
Labialle S, Gayet L, Marthinet E, Rigal D, Baggetto LG (2002) Transcriptional regulators of the human multidrug resistance 1 gene: recent views. Biochem Pharmacol 64:943–948
Scotto KW (2003) Transcriptional regulation of ABC drug transporters. Oncogene 22:7496–7511
Umbenhauer DR, Lankas GR, Pippert TR et al (1997) Identification of a P-glycoprotein-deficient subpopulation in the CF-1 mouse strain using a restriction fragment length polymorphism. Toxicol Appl Pharmacol 146:88–94
Hoffmeyer S, Burk O, von Richter O et al (2000) Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo. Proc Natl Acad Sci USA 97:3473–3478
Kimchi-Sarfaty C, Oh JM, Kim IW et al (2007) A “silent” polymorphism in the MDR1 gene changes substrate specificity. Science 315:525–528
Wang D, Sadee W (2006) Searching for polymorphisms that affect gene expression and mRNA processing: example ABCB1 (MDR1). AAPS J 8:E515–E520
Streetman DS (2007) Clinical pharmacogenetics of the major adenosine triphosphate binding cassette and solute carrier drug transporters. J Pharm Pract 20:219–233
Takano M, Yumoto R, Murakami T (2006) Expression and function of efflux drug transporters in the intestine. Pharmacol Ther 109:137–161
Fojo AT, Ueda K, Slamon DJ et al (1987) Expression of a multidrug-resistance gene in human tumors and tissues. Proc Natl Acad Sci USA 84:265–269
Augustijns PF, Bradshaw TP, Gan LS, Hendren RW, Thakker DR (1993) Evidence for a polarized efflux system in CACO-2 cells capable of modulating cyclosporin A transport. Biochem Biophys Res Commun 197:360–365
Burton PS, Conradi RA, Hilgers AR, Ho NF (1993) Evidence for a polarized efflux system for peptides in the apical membrane of Caco-2 cells. Biochem Biophys Res Commun 190:760–766
Hunter J, Hirst BH, Simmons NL (1993) Drug absorption limited by P-glycoprotein-mediated secretory drug transport in human intestinal epithelial Caco-2 cell layers. Pharm Res 10:743–749
Hunter J, Jepson MA, Tsuruo T, Simmons NL, Hirst BH (1993) Functional expression of P-glycoprotein in apical membranes of human intestinal Caco-2 cells. Kinetics of vinblastine secretion and interaction with modulators. J Biol Chem 268:14991–14997
Sparreboom A, van Asperen J, Mayer U et al (1997) Limited oral bioavailability and active epithelial excretion of paclitaxel (Taxol) caused by P-glycoprotein in the intestine. Proc Natl Acad Sci USA 94:2031–2035
Meerum Terwogt JM, Malingre MM, Beijnen JH et al (1999) Coadministration of oral cyclosporin A enables oral therapy with paclitaxel. Clin Cancer Res 5:3379–3384
Malingre MM, Richel DJ, Beijnen JH et al (2001) Coadministration of cyclosporine strongly enhances the oral bioavailability of docetaxel. J Clin Oncol 19:1160–1166
Mayer U, Wagenaar E, Beijnen JH et al (1996) Substantial excretion of digoxin via the intestinal mucosa and prevention of long-term digoxin accumulation in the brain by the mdr 1a P-glycoprotein. Br J Pharmacol 119:1038–1044
Drescher S, Glaeser H, Murdter T et al (2003) P-glycoprotein-mediated intestinal and biliary digoxin transport in humans. Clin Pharmacol Ther 73:223–231
Chiou WL, Chung SM, Wu TC, Ma C (2001) A comprehensive account on the role of efflux transporters in the gastrointestinal absorption of 13 commonly used substrate drugs in humans. Int J Clin Pharmacol Ther 39:93–101
Lin JH, Yamazaki M (2003) Role of P-glycoprotein in pharmacokinetics: clinical implications. Clin Pharmacokinet 42:59–98
Lown KS, Mayo RR, Leichtman AB et al (1997) Role of intestinal P-glycoprotein (mdr1) in interpatient variation in the oral bioavailability of cyclosporine. Clin Pharmacol Ther 62:248–260
Masuda S, Uemoto S, Hashida T et al (2000) Effect of intestinal P-glycoprotein on daily tacrolimus trough level in a living-donor small bowel recipient. Clin Pharmacol Ther 68:98–103
Benet LZ, Izumi T, Zhang Y, Silverman JA, Wacher VJ (1999) Intestinal MDR transport proteins and P-450 enzymes as barriers to oral drug delivery. J Control Release 62:25–31
Wacher VJ, Salphati L, Benet LZ (2001) Active secretion and enterocytic drug metabolism barriers to drug absorption. Adv Drug Deliv Rev 46:89–102
Lin JH, Chiba M, Chen IW et al (1999) Effect of dexamethasone on the intestinal first-pass metabolism of indinavir in rats: evidence of cytochrome P-450 3A (correction of P-450 A) and p-glycoprotein induction. Drug Metab Dispos 27:1187–1193
Loscher W, Potschka H (2005) Blood–brain barrier active efflux transporters: ATP-binding cassette gene family. NeuroRx 2:86–98
Levin VA (1980) Relationship of octanol/water partition coefficient and molecular weight to rat brain capillary permeability. J Med Chem 23:682–684
Tsuji A, Tamai I (1997) Blood–brain barrier function of P-glycoprotein. Adv Drug Deliv Rev 25:287–298
Cordon-Cardo C, O’Brien JP, Casals D et al (1989) Multidrug-resistance gene (P-glycoprotein) is expressed by endothelial cells at blood–brain barrier sites. Proc Natl Acad Sci USA 86:695–698
Thiebaut F, Tsuruo T, Hamada H et al (1989) Immunohistochemical localization in normal tissues of different epitopes in the multidrug transport protein P170: evidence for localization in brain capillaries and crossreactivity of one antibody with a muscle protein. J Histochem Cytochem 37:159–164
Beaulieu E, Demeule M, Ghitescu L, Beliveau R (1997) P-glycoprotein is strongly expressed in the luminal membranes of the endothelium of blood vessels in the brain. Biochem J 326(Pt 2):539–544
Decleves X, Regina A, Laplanche JL et al (2000) Functional expression of P-glycoprotein and multidrug resistance-associated protein (Mrp1) in primary cultures of rat astrocytes. J Neurosci Res 60:594–601
Pardridge WM, Golden PL, Kang YS, Bickel U (1997) Brain microvascular and astrocyte localization of P-glycoprotein. J Neurochem 68:1278–1285
Lee G, Schlichter L, Bendayan M, Bendayan R (2001) Functional expression of P-glycoprotein in rat brain microglia. J Pharmacol Exp Ther 299:204–212
Tatsuta T, Naito M, Oh-hara T, Sugawara I, Tsuruo T (1992) Functional involvement of P-glycoprotein in blood–brain barrier. J Biol Chem 267:20383–20391
Tsuji A, Terasaki T, Takabatake Y et al (1992) P-glycoprotein as the drug efflux pump in primary cultured bovine brain capillary endothelial cells. Life Sci 51:1427–1437
Ohnishi T, Tamai I, Sakanaka K et al (1995) In vivo and in vitro evidence for ATP-dependency of P-glycoprotein-mediated efflux of doxorubicin at the blood–brain barrier. Biochem Pharmacol 49:1541–1544
Schinkel AH (1999) P-Glycoprotein, a gatekeeper in the blood–brain barrier. Adv Drug Deliv Rev 36:179–194
Bartels AL, Kortekaas R, Bart J et al (2008) Blood–brain barrier P-glycoprotein function decreases in specific brain regions with aging: a possible role in progressive neurodegeneration. Neurobiol Aging
Tishler DM, Weinberg KI, Hinton DR et al (1995) MDR1 gene expression in brain of patients with medically intractable epilepsy. Epilepsia 36:1–6
Loscher W (2007) Drug transporters in the epileptic brain. Epilepsia 48(Suppl 1):8–13
Sadeque AJ, Wandel C, He H, Shah S, Wood AJ (2000) Increased drug delivery to the brain by P-glycoprotein inhibition. Clin Pharmacol Ther 68:231–237
Kharasch ED, Hoffer C, Whittington D (2004) The effect of quinidine, used as a probe for the involvement of P-glycoprotein, on the intestinal absorption and pharmacodynamics of methadone. Br J Clin Pharmacol 57:600–610
Troger U, Lins H, Scherrmann JM, Wallesch CW, Bode-Boger SM (2005) Tetraparesis associated with colchicine is probably due to inhibition by verapamil of the P-glycoprotein efflux pump in the blood–brain barrier. BMJ 331:613
Enders AC, Blankenship TN (1999) Comparative placental structure. Adv Drug Deliv Rev 38:3–15
van der Aa EM, Peereboom-Stegeman JH, Noordhoek J, Gribnau FW, Russel FG (1998) Mechanisms of drug transfer across the human placenta. Pharm World Sci 20:139–148
Audus KL (1999) Controlling drug delivery across the placenta. Eur J Pharm Sci 8:161–165
Pacifici GM, Nottoli R (1995) Placental transfer of drugs administered to the mother. Clin Pharmacokinet 28:235–269
Kalabis GM, Kostaki A, Andrews MH et al (2005) Multidrug resistance phosphoglycoprotein (ABCB1) in the mouse placenta: fetal protection. Biol Reprod 73:591–597
Novotna M, Libra A, Kopecky M et al (2004) P-glycoprotein expression and distribution in the rat placenta during pregnancy. Reprod Toxicol 18:785–792
Sun M, Kingdom J, Baczyk D et al (2006) Expression of the multidrug resistance P-glycoprotein, (ABCB1 glycoprotein) in the human placenta decreases with advancing gestation. Placenta 27:602–609
Gil S, Saura R, Forestier F, Farinotti R (2005) P-glycoprotein expression of the human placenta during pregnancy. Placenta 26:268–270
Nanovskaya TN, Nekhayeva IA, Hankins GD, Ahmed MS (2008) Transfer of methadone across the dually perfused preterm human placental lobule. Am J Obstet Gynecol 198(126):e121–e124
Nakamura Y, Ikeda S, Furukawa T et al (1997) Function of P-glycoprotein expressed in placenta and mole. Biochem Biophys Res Commun 235:849–853
Utoguchi N, Chandorkar GA, Avery M, Audus KL (2000) Functional expression of P-glycoprotein in primary cultures of human cytotrophoblasts and BeWo cells. Reprod Toxicol 14:217–224
Ushigome F, Takanaga H, Matsuo H et al (2000) Human placental transport of vinblastine, vincristine, digoxin and progesterone: contribution of P-glycoprotein. Eur J Pharmacol 408:1–10
Lankas GR, Wise LD, Cartwright ME, Pippert T, Umbenhauer DR (1998) Placental P-glycoprotein deficiency enhances susceptibility to chemically induced birth defects in mice. Reprod Toxicol 12:457–463
Smit JW, Huisman MT, van Tellingen O, Wiltshire HR, Schinkel AH (1999) Absence or pharmacological blocking of placental P-glycoprotein profoundly increases fetal drug exposure. J Clin Invest 104:1441–1447
Huisman MT, Smit JW, Wiltshire HR et al (2001) P-glycoprotein limits oral availability, brain, and fetal penetration of saquinavir even with high doses of ritonavir. Mol Pharmacol 59:806–813
Pavek P, Fendrich Z, Staud F et al (2001) Influence of P-glycoprotein on the transplacental passage of cyclosporine. J Pharm Sci 90:1583–1592
Pavek P, Staud F, Fendrich Z et al (2003) Examination of the functional activity of P-glycoprotein in the rat placental barrier using rhodamine 123. J Pharmacol Exp Ther 305:1239–1250
Holcberg G, Sapir O, Tsadkin M et al (2003) Lack of interaction of digoxin and P-glycoprotein inhibitors, quinidine and verapamil in human placenta in vitro. Eur J Obstet Gynecol Reprod Biol 109:133–137
Sudhakaran S, Ghabrial H, Nation RL et al (2005) Differential bidirectional transfer of indinavir in the isolated perfused human placenta. Antimicrob Agents Chemother 49:1023–1028
Sudhakaran S, Rayner CR, Li J et al (2008) Inhibition of placental P-glycoprotein: impact on indinavir transfer to the foetus. Br J Clin Pharmacol 65:667–673
Molsa M, Heikkinen T, Hakkola J et al (2005) Functional role of P-glycoprotein in the human blood–placental barrier. Clin Pharmacol Ther 78:123–131
Rahi M, Heikkinen T, Hakkola J et al (2008) Influence of adenosine triphosphate and ABCB1 (MDR1) genotype on the P-glycoprotein-dependent transfer of saquinavir in the dually perfused human placenta. Hum Exp Toxicol 27:65–71
Nekhayeva IA, Nanovskaya TN, Deshmukh SV et al (2005) Bidirectional transfer of methadone across human placenta. Biochem Pharmacol 69:187–197
Nanovskaya T, Nekhayeva I, Karunaratne N et al (2005) Role of P-glycoprotein in transplacental transfer of methadone. Biochem Pharmacol 69:1869–1878
Nekhayeva IA, Nanovskaya TN, Hankins GD, Ahmed MS (2006) Role of human placental efflux transporter P-glycoprotein in the transfer of buprenorphine, levo-alpha-acetylmethadol, and paclitaxel. Am J Perinatol 23:423–430
Kolwankar D, Glover DD, Ware JA, Tracy TS (2005) Expression and function of ABCB1 and ABCG2 in human placental tissue. Drug Metab Dispos 33:524–529
Tanabe M, Ieiri I, Nagata N et al (2001) Expression of P-glycoprotein in human placenta: relation to genetic polymorphism of the multidrug resistance (MDR)-1 gene. J Pharmacol Exp Ther 297:1137–1143
Hitzl M, Schaeffeler E, Hocher B et al (2004) Variable expression of P-glycoprotein in the human placenta and its association with mutations of the multidrug resistance 1 gene (MDR1, ABCB1). Pharmacogenetics 14:309–318
Brown KR (1998) Changes in the use profile of Mectizan: 1987–1997. Ann Trop Med Parasitol 92(Suppl 1):S61–S64
Gadducci A, Cosio S, Fanucchi A et al (2003) Chemotherapy with epirubicin and paclitaxel for breast cancer during pregnancy: case report and review of the literature. Anticancer Res 23:5225–5229
Kleinman CS, Nehgme RA (2004) Cardiac arrhythmias in the human fetus. Pediatr Cardiol 25:234–251
Oudijk MA, Ruskamp JM, Ambachtsheer BE et al (2002) Drug treatment of fetal tachycardias. Paediatr Drugs 4:49–63
Capparelli E, Rakhmanina N, Mirochnick M (2005) Pharmacotherapy of perinatal HIV. Semin Fetal Neonatal Med 10:161–175
Clayette P, Jorajuria S, Dormont D (2000) Significance of P-glycoprotein for the pharmacology and clinical use of HIV protease inhibitors. AIDS 14:235–236
Ito S (2001) Transplacental treatment of fetal tachycardia: implications of drug transporting proteins in placenta. Semin Perinatol 25:196–201
Ploen L, Setchell BP (1992) Blood–testis barriers revisited. A homage to Lennart Nicander. Int J Androl 15:1–4
Setchell BP, Main SJ (1978) Drugs and the blood–testis barrier. Environ Health Perspect 24:61–64
Baas F, Borst P (1988) The tissue dependent expression of hamster P-glycoprotein genes. FEBS Lett 229:329–332
Trezise AE, Romano PR, Gill DR et al (1992) The multidrug resistance and cystic fibrosis genes have complementary patterns of epithelial expression. EMBO J 11:4291–4303
Sugawara I, Akiyama S, Scheper RJ, Itoyama S (1997) Lung resistance protein (LRP) expression in human normal tissues in comparison with that of MDR1 and MRP. Cancer Lett 112:23–31
Melaine N, Lienard MO, Dorval I et al (2002) Multidrug resistance genes and p-glycoprotein in the testis of the rat, mouse, Guinea pig, and human. Biol Reprod 67:1699–1707
Lankas GR, Cartwright ME, Umbenhauer D (1997) P-glycoprotein deficiency in a subpopulation of CF-1 mice enhances avermectin-induced neurotoxicity. Toxicol Appl Pharmacol 143:357–365
Hughes CS, Vaden SL, Manaugh CA, Price GS, Hudson LC (1998) Modulation of doxorubicin concentration by cyclosporin A in brain and testicular barrier tissues expressing P-glycoprotein in rats. J Neurooncol 37:45–54
Choo EF, Leake B, Wandel C et al (2000) Pharmacological inhibition of P-glycoprotein transport enhances the distribution of HIV-1 protease inhibitors into brain and testes. Drug Metab Dispos 28:655–660
Choo EF, Kurnik D, Muszkat M et al (2006) Differential in vivo sensitivity to inhibition of P-glycoprotein located in lymphocytes, testes, and the blood–brain barrier. J Pharmacol Exp Ther 317:1012–1018
Kreuser ED, Hetzel WD, Billia DO, Thiel E (1990) Gonadal toxicity following cancer therapy in adults: significance, diagnosis, prevention and treatment. Cancer Treat Rev 17:169–175
Viviani S, Santoro A, Ragni G et al (1985) Gonadal toxicity after combination chemotherapy for Hodgkin’s disease. Comparative results of MOPP vs ABVD. Eur J Cancer Clin Oncol 21:601–605
Sharpe RM (1993) Declining sperm counts in men – is there an endocrine cause? J Endocrinol 136:357–360
Sharpe RM, Fisher JS, Millar MM, Jobling S, Sumpter JP (1995) Gestational and lactational exposure of rats to xenoestrogens results in reduced testicular size and sperm production. Environ Health Perspect 103:1136–1143
Roberts MS, Magnusson BM, Burczynski FJ, Weiss M (2002) Enterohepatic circulation: physiological, pharmacokinetic and clinical implications. Clin Pharmacokinet 41:751–790
Kojima T, Yamamoto T, Murata M et al (2003) Regulation of the blood–biliary barrier: interaction between gap and tight junctions in hepatocytes. Med Electron Microsc 36:157–164
Kamimoto Y, Gatmaitan Z, Hsu J, Arias IM (1989) The function of Gp170, the multidrug resistance gene product, in rat liver canalicular membrane vesicles. J Biol Chem 264:11693–11698
Watanabe T, Miyauchi S, Sawada Y et al (1992) Kinetic analysis of hepatobiliary transport of vincristine in perfused rat liver. Possible roles of P-glycoprotein in biliary excretion of vincristine. J Hepatol 16:77–88
Schinkel AH, Mayer U, Wagenaar E et al (1997) Normal viability and altered pharmacokinetics in mice lacking mdr1-type (drug-transporting) P-glycoproteins. Proc Natl Acad Sci USA 94:4028–4033
Meier Y, Pauli-Magnus C, Zanger UM et al (2006) Interindividual variability of canalicular ATP-binding-cassette (ABC)-transporter expression in human liver. Hepatology 44:62–74
Cascorbi I (2006) Role of pharmacogenetics of ATP-binding cassette transporters in the pharmacokinetics of drugs. Pharmacol Ther 112:457–473
Marzolini C, Paus E, Buclin T, Kim RB (2004) Polymorphisms in human MDR1 (P-glycoprotein): recent advances and clinical relevance. Clin Pharmacol Ther 75:13–33
Kakumoto M, Takara K, Sakaeda T et al (2002) MDR1-mediated interaction of digoxin with antiarrhythmic or antianginal drugs. Biol Pharm Bull 25:1604–1607
Wakasugi H, Yano I, Ito T et al (1998) Effect of clarithromycin on renal excretion of digoxin: interaction with P-glycoprotein. Clin Pharmacol Ther 64:123–128
Boyd RA, Stern RH, Stewart BH et al (2000) Atorvastatin coadministration may increase digoxin concentrations by inhibition of intestinal P-glycoprotein-mediated secretion. J Clin Pharmacol 40:91–98
Greiner B, Eichelbaum M, Fritz P et al (1999) The role of intestinal P-glycoprotein in the interaction of digoxin and rifampin. J Clin Invest 104:147–153
Micuda S, Brcakova E, Fuksa L et al (2008) P-glycoprotein function and expression during obstructive cholestasis in rats. Eur J Gastroenterol Hepatol 20:404–412
Zollner G, Fickert P, Silbert D et al (2003) Adaptive changes in hepatobiliary transporter expression in primary biliary cirrhosis. J Hepatol 38:717–727
Zollner G, Wagner M, Fickert P et al (2005) Hepatobiliary transporter expression in human hepatocellular carcinoma. Liver Int 25:367–379
Hidemura K, Zhao YL, Ito K et al (2003) Shiga-like toxin II impairs hepatobiliary transport of doxorubicin in rats by down-regulation of hepatic P glycoprotein and multidrug resistance-associated protein Mrp2. Antimicrob Agents Chemother 47:1636–1642
Pavek P, Dvorak Z (2008) Xenobiotic-induced transcriptional regulation of xenobiotic metabolizing enzymes of the cytochrome P450 superfamily in human extrahepatic tissues. Curr Drug Metab 9:129–143
Lash LH, Putt DA, Cai H (2008) Drug metabolism enzyme expression and activity in primary cultures of human proximal tubular cells. Toxicology 244:56–65
Launay-Vacher V, Izzedine H, Karie S et al (2006) Renal tubular drug transporters. Nephron Physiol 103:p97–p106
Hori R, Okamura N, Aiba T, Tanigawara Y (1993) Role of P-glycoprotein in renal tubular secretion of digoxin in the isolated perfused rat kidney. J Pharmacol Exp Ther 266:1620–1625
Micuda S, Fuksa L, Mundlova L et al (2007) Morphological and functional changes in p-glycoprotein during dexamethasone-induced hepatomegaly. Clin Exp Pharmacol Physiol 34:296–303
Kawahara M, Sakata A, Miyashita T, Tamai I, Tsuji A (1999) Physiologically based pharmacokinetics of digoxin in mdr1a knockout mice. J Pharm Sci 88:1281–1287
Sasabe H, Kato Y, Suzuki T et al (2004) Differential involvement of multidrug resistance-associated protein 1 and P-glycoprotein in tissue distribution and excretion of grepafloxacin in mice. J Pharmacol Exp Ther 310:648–655
Smit JW, Schinkel AH, Weert B, Meijer DK (1998) Hepatobiliary and intestinal clearance of amphiphilic cationic drugs in mice in which both mdr1a and mdr1b genes have been disrupted. Br J Pharmacol 124:416–424
Angirasa AK, Koch AZ (2002) P-glycoprotein as the mediator of itraconazole–digoxin interaction. J Am Podiatr Med Assoc 92:471–472
Rengelshausen J, Goggelmann C, Burhenne J et al (2003) Contribution of increased oral bioavailability and reduced nonglomerular renal clearance of digoxin to the digoxin–clarithromycin interaction. Br J Clin Pharmacol 56:32–38
Linnet K, Ejsing TB (2008) A review on the impact of P-glycoprotein on the penetration of drugs into the brain. Eur Neuropsychopharmacol 18:157–169
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Staud, F., Ceckova, M., Micuda, S., Pavek, P. (2010). Expression and Function of P-Glycoprotein in Normal Tissues: Effect on Pharmacokinetics. In: Zhou, J. (eds) Multi-Drug Resistance in Cancer. Methods in Molecular Biology, vol 596. Humana Press. https://doi.org/10.1007/978-1-60761-416-6_10
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