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Role of P-Glycoprotein in Pharmacokinetics

Clinical Implications

  • Review Article
  • Drug Disposition
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Abstract

P-glycoprotein, the most extensively studied ATP-binding cassette (ABC) transporter, functions as a biological barrier by extruding toxins and xenobiotics out of cells. In vitro and in vivo studies have demonstrated that P-glycoprotein plays a significant role in drug absorption and disposition. Because of its localisation, P-glycoprotein appears to have a greater impact on limiting cellular uptake of drugs from blood circulation into brain and from intestinal lumen into epithelial cells than on enhancing the excretion of drugs out of hepatocytes and renal tubules into the adjacent luminal space. However, the relative contribution of intestinal P-glycoprotein to overall drug absorption is unlikely to be quantitatively important unless a very small oral dose is given, or the dissolution and diffusion rates of the drug are very slow. This is because P-glycoprotein transport activity becomes saturated by high concentrations of drug in the intestinal lumen.

Because of its importance in pharmacokinetics, P-glycoprotein transport screening has been incorporated into the drug discovery process, aided by the availability of transgenic mdr knockout mice and in vitro cell systems. When applying in vitro and in vivo screening models to study P-glycoprotein function, there are two fundamental questions: (i) can in vitro data be accurately extrapolated to the in vivo situation; and (ii) can animal data be directly scaled up to humans? Current information from our laboratory suggests that in vivo P-glycoprotein activity for a given drug can be extrapolated reasonably well from in vitro data. On the other hand, there are significant species differences in P-glycoprotein transport activity between humans and animals, and the species differences appear to be substrate-dependent.

Inhibition and induction of P-glycoprotein have been reported as the causes of drug-drug interactions. The potential risk of P-glycoprotein-mediated drug interactions may be greatly underestimated if only plasma concentration is monitored. From animal studies, it is clear that P-glycoprotein inhibition always has a much greater impact on tissue distribution, particularly with regard to the brain, than on plasma concentrations. Therefore, the potential risk of P-glycoprotein-mediated drug interactions should be assessed carefully. Because of overlapping substrate specificity between cytochrome P450 (CYP) 3A4 and P-glycoprotein, and because of similarities in P-glycoprotein and CYP3A4 inhibitors and inducers, many drug interactions involve both P-glycoprotein and CYP3A4. Unless the relative contribution of P-glycoprotein and CYP3A4 to drug interactions can be quantitatively estimated, care should be taken when exploring the underlying mechanism of such interactions.

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References

  1. Juliano RL, Ling V. A surface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutants. Biochim Biophys Acta 1976; 455: 152–62

    PubMed  CAS  Google Scholar 

  2. Gottesman MM, Pastan I. Biochemistry of multidrug resistance mediated by the multidrug transporter. Annu Rev Biochem 1993; 62: 385–427

    PubMed  CAS  Google Scholar 

  3. Schinkel AH. The physiological function of drug-transporting P-glycoproteins. Cancer Biol 1997; 8: 161–70

    CAS  Google Scholar 

  4. van Helvoort A, Smith AJ, Sprong H, et al. MDR1 P-glycoprotein is a lipid translocase of broad specificity, while MDR3 P-glycoprotein specifically translocates phosphatidylcholine. Cell 1996; 87: 507–17

    PubMed  Google Scholar 

  5. Ruetz S, Gros P. Phosphatidylcholine translocase: a physiological role for the mdr 2 gene. Cell 1994; 77: 1071–81

    PubMed  CAS  Google Scholar 

  6. Smith AJ, van Helvoort A, van Meer G, et al. MDR3 P-glycoprotein, a phosphatidylcholine translocase, transports several cytotoxic drugs and directly interacts with drugs as judged by interference with nucleotide trapping. J Biol Chem 2000; 275: 23530–9

    PubMed  CAS  Google Scholar 

  7. Thiebaut F, Tsuruo T, Hamada H, et al. Cellular localization of the multidrug resistance gene product P-glycoprotein in normal human tissues. Proc Natl Acad Sci U S A 1987; 84: 7735–8

    PubMed  CAS  Google Scholar 

  8. Cordon-Cardo C, O’Brien JP, Boccia J, et al. Expression of the multidrug resistance gene product (P-glycoprotein) in human normal and tumor tissues. J Histochem Cytochem 1990; 38: 1277–87

    PubMed  CAS  Google Scholar 

  9. Schinkel AH, Smit JJM, van Tellingen O, et al. Disruption of the mouse mdr la P-glycoprotein gene leads to a deficiency in the blood-brain barrier and to increased sensitivity to drugs. Cell 1994; 77: 491–502

    PubMed  CAS  Google Scholar 

  10. Schinkel AH, Mayer U, Wagenaar E, et al. Normal viability and altered pharmacokinetics in mice lacking mdrl-type (drug-transporting) P-glycoproteins. Proc Natl Acad Sci USA 1997; 94: 4028–33

    PubMed  CAS  Google Scholar 

  11. Chen C-J, Chin JE, Ueda K, et al. Internal duplication and homology with bacterial transport proteins in mdr1 (P-glycoprotein) gene from multidrug-resistant human cells. Cell 1986; 47: 381–9

    PubMed  CAS  Google Scholar 

  12. Loo TW, Clarke DM. Reconstitution of drug-stimulated ATPase activity following co-expression of each half of human P-glycoprotein as separate polypeptides. J Biol Chem 1994; 269: 7750–5

    PubMed  CAS  Google Scholar 

  13. Muller M, Bakos E, Welker E, et al. Altered drug-stimulated ATPase activity in mutants of human multidrug resistance protein. J Biol Chem 1996; 271: 1877–83

    PubMed  CAS  Google Scholar 

  14. Takada Y, Yamada K, Taguchi Y, et al. Non-equivalent cooperation between the two nucleotide binding folds of P-glycoprotein. Biochim Biophys Acta 1998; 1373: 131–6

    PubMed  CAS  Google Scholar 

  15. Hrycyna CA, Arian LE, Germann UA, et al. Structural flexibility of the linker region of human P-glycoprotein permits ATP hydrolysis and drug transport. Biochemistry 1998; 37: 13660–73

    PubMed  CAS  Google Scholar 

  16. Ford JM, Hait WN. Pharmacology of drugs that alter multidrug resistance in cancer. Pharmacol Rev 1990; 42: 155–99

    PubMed  CAS  Google Scholar 

  17. Homolya L, Hollo Z, Germann UA, et al. Fluorescent cellular indicators are extruded by the multidrug resistance protein. J Biol Chem 1993; 268: 21493–6

    PubMed  CAS  Google Scholar 

  18. Shapiro AB, Ling V. Extraction of Hoechst 33342 from the cytoplasmic leaflet of the plasma membrane by P-glycoprotein. Eur J Biochem 1997; 250: 122–9

    PubMed  CAS  Google Scholar 

  19. Higgins CF, Gottesman MM. Is the multidrug transporter a flippase?. Trends Biochem Sci 1992; 17: 18–21

    PubMed  CAS  Google Scholar 

  20. Rosenberg MF, Callaghan R, Ford RC, et al. Structure of multidrug resistance P-glycoprotein to 2.5 nm resolution determined by electron microscopy and image analysis. J Biol Chem 1997; 272: 10685–94

    PubMed  CAS  Google Scholar 

  21. Hung LW, Wang IX, Nikaido K, et al. Crystal structure of the ATP-binding subunit of an ABC transporter. Nature 1998; 396: 703–7

    PubMed  CAS  Google Scholar 

  22. Ambudkar SV, Dey S, Hrycyna CA, et al. Biochemical, cellular, and pharmacological aspects of the multidrug transporter. Annu Rev Pharmacol Toxicol 1999; 39: 361–98

    PubMed  CAS  Google Scholar 

  23. Schurr E, Raymond M, Bell JC, et al. Characterization of the multidrug resistance protein expressed in cell clones stably transfected with the mouse mdr cDNA. Cancer Res 1989; 49: 2729–34

    PubMed  CAS  Google Scholar 

  24. Senior AE, Gadsby DC. ATP hydrolysis cycles and mechanism in P-glycoprotein and CFTR. Semin Cancer Biol 1997; 8: 143–50

    PubMed  CAS  Google Scholar 

  25. Shapiro AB, Ling V. Stoichiometry of coupling of rhodamine 123 transport to ATP hydrolysis by P-glycoprotein. Eur J Biochem 1998; 254: 189–93

    PubMed  CAS  Google Scholar 

  26. Ambudkar SV, Cardarelli CO, Pashinsky I, et al. Relationship between the turnover number for vinblastine transport and for vinblastine-stimulated ATP hydrolysis by human P-glycoprotein. J Biol Chem 1997; 272: 21160–6

    PubMed  CAS  Google Scholar 

  27. Greenberger LM. Major photoaffinity drug labeling sites for iodoaryl azidoprazosin in P-glycoprotein are within or immediately C-terminal to transmembrane domains 6 and 12. J Biol Chem 1993; 268: 11417–25

    PubMed  CAS  Google Scholar 

  28. Bruggemann EP, Germann UA, Gottesman MM, et al. Two different regions of phosphoglycoprotein are photoaffinity-labeled by azidopine. J Biol Chem 1989; 264: 15483–8

    PubMed  Google Scholar 

  29. Wu Q, Bounaud P, Kudul S, et al. Identification of the domains of photoincorporation of the 3′- and 7-benzophenone analogues of taxol in the carboxyl-terminal half of murine mdrlb P-glycoprotein. Biochemistry 1998; 37: 11272–9

    PubMed  CAS  Google Scholar 

  30. Ueda K, Taguchi Y, Morishima M. How does P-gp recognize its substrates?. Semin Cancer Biol 1997; 8: 151–9

    PubMed  CAS  Google Scholar 

  31. Taguchi Y, Kino K, Morishima M, et al. Alteration of substrate specificity by mutations at the His61 position in predicted transmembrane domain 1 of human MDR1/P-glycoprotein. Biochemistry 1997; 36: 8883–9

    PubMed  CAS  Google Scholar 

  32. Taguchi Y, Morishima M, Komano T, et al. Amino acid substitutions in the first transmembrane domain (TM1) of P-glycoprotein alter substrate specificity. FEBS Lett 1997; 413: 142–6

    PubMed  CAS  Google Scholar 

  33. Loo TW, Clarke DM. Functional consequences of glycine mutations in the predicted cytoplasmic loops of P-glycoprotein. J Biol Chem 1994; 269: 7243–8

    PubMed  CAS  Google Scholar 

  34. Currier SJ, Kane SE, Willingham MC, et al. Identification of residues in the first cytoplasmic loop of P-glycoprotein involved in the function of chimeric human MDR1-MDR2 transporters. J Biol Chem 1992; 267: 25153–9

    PubMed  CAS  Google Scholar 

  35. Pan B-F, Dutt A, Nelson JA. Enhanced transepithelial flux of cimetidine by Madin-Darby canine kidney cells overexpressing human P-glycoprotein. J Pharmacol Exp Ther 1994; 270: 1–7

    PubMed  CAS  Google Scholar 

  36. Wu C-Y, Benet LZ, Hebert MF, et al. Differentiation of absorption and first-pass gut and hepatic metabolism in humans: studies with cyclosporine. Clin Pharmacol Ther 1995; 58: 492–7

    PubMed  CAS  Google Scholar 

  37. Tang-Wai DF, Brossi A, Arnold LD, et al. The nitrogen of the acetamido group of colchicine modulates P-glycoprotein-mediated multidrug resistance. Biochemistry 1993; 32: 6470–6

    PubMed  CAS  Google Scholar 

  38. Ueda K, Okamura N, Hirai M, et al. Human P-glycoprotein transports Cortisol, aldosterone, and dexamethasone, but not progesterone. J Biol Chem 1992; 267: 24248–52

    PubMed  CAS  Google Scholar 

  39. Chiba P, Holzer W, Landau M, et al. Substituted 4-acylpyrazoles and 4-acylpyrazolones: synthesis and multidrug resistance-modulating activity. J Med Chem 1998; 41: 4001–11

    PubMed  CAS  Google Scholar 

  40. Ecker G, Huber M, Schmid D, et al. The importance of a nitrogen atom in modulators of multidrug resistance. Mol Pharmacol 1999; 56: 791–6

    PubMed  CAS  Google Scholar 

  41. Seelig A, Landwojtowicz E. Structure-activity relationship of P-glycoprotein substrates and modifiers. Eur J Pharm Sci 2000; 12: 31–40

    PubMed  CAS  Google Scholar 

  42. Seelig A. How does P-glycoprotein recognize its substrates?. Int J Clin Pharmacol Ther 1998; 36: 50–4

    PubMed  CAS  Google Scholar 

  43. Osterberg T, Norinder U. Theoretical calculation and prediction of P-glycoprotein-interacting drugs using MolSurf parametrization and PLS statistics. Eur J Pharm Sci 2000; 10: 295–303

    PubMed  CAS  Google Scholar 

  44. Chiba P, Ecker G, Schmid D, et al. Structural requirements for activity of propafenone-type modulators in P-glycoprotein-mediated multidrug resistance. Mol Pharmacol 1996; 49: 1122–30

    PubMed  CAS  Google Scholar 

  45. Lin JH, Lu AYH. Interindividual variability in inhibition and induction of cytochrome P450 enzymes. Annu Rev Pharmacol Toxicol 2001; 41: 535–67

    PubMed  CAS  Google Scholar 

  46. Lankas GR, Cartwright ME, Umbenhauer DR. P-glycoprotein deficiency in a subpopulation of CF-1 mice enhances avermectin-induced neurotoxicity. Toxicol Appl Pharmacol 1997; 143: 357–65

    PubMed  CAS  Google Scholar 

  47. Umbenhauer DR, Lankas GR, Pippert TR, et al. Identification of a P-glycoprotein-deficient subpopulation in CF-1 mouse strain using a restriction fragment length polymorphism. Toxicol Appl Pharmacol 1997; 146: 88–94

    PubMed  CAS  Google Scholar 

  48. Lankas GR, Wise LD, Cartwright ME, et al. Placenta P-glycoprotein deficiency enhances susceptibility to chemically induced birth defects in mice. Reprod Toxicol 1998; 12: 457–63

    PubMed  CAS  Google Scholar 

  49. Pippert TR, Umbenhauer DR. The subpopulation of CF-1 mice deficient in P-glycoprotein contains a murine retroviral insertion in the mdr1agene. J Biochem Mol Toxicol 2001; 15: 83–9

    PubMed  CAS  Google Scholar 

  50. Pulliam JD, Seward RL, Henry RT, et al. Investigating ivermectin toxicity in Collies. Vet Med 1985; 80: 33–40

    Google Scholar 

  51. Paul AJ, Tranquilli WJ, Seward RL, et al. Clinical observations in Collies given ivermectin orally. Am J Vet Res 1987; 48: 684–5

    PubMed  CAS  Google Scholar 

  52. Mealey KL, Bentjen SA, Gay JM, et al. Ivermectin sensitivity in collies is associated with a deletion mutation of the mdr1 gene. Pharmacogenetics 2001; 11: 727–33

    PubMed  CAS  Google Scholar 

  53. Kioka N, Tsubota J, Kakehi Y, et al. P-glycoprotein gene (MDR1) cDNA from human adrenal: normal P-glycoprotein carries Glyl85 with an altered pattern of multidrug resistance. Biochem Biophys Res Commun 1989; 162: 224–31

    PubMed  CAS  Google Scholar 

  54. Mickley LA, Lee J-S, Weng Z, et al. Genetic polymorphism in MDR-1: a tool for examining allelic expression in normal cells, unselected and drug-selected cell lines, and human tumors. Blood 1998; 91: 1749–56

    PubMed  CAS  Google Scholar 

  55. Hoffmeyer S, Burk O, von Richter O, et al. 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 2000; 97: 3473–8

    PubMed  CAS  Google Scholar 

  56. Sakaeda T, Nakamura T, Horinouchi M, et al. MDR1 genotyperelated pharmacokinetics of digoxin after single oral administration in healthy Japanese subjects. Pharm Res 2001; 18: 1400–4

    PubMed  CAS  Google Scholar 

  57. Kim RB, Leake BF, Choo EF, et al. Identification of functionally variant MDR1 alleles among European Americans and African Americans. Clin Pharmacol Ther 2001; 70: 189–99

    PubMed  CAS  Google Scholar 

  58. Drescher S, Schaeffeler E, Hitzl M, et al. MDR1 gene polymorphisms and disposition of the P-glycoprotein substrate fexofenadine. Br J Clin Pharmacol 2002; 53: 526–34

    PubMed  CAS  Google Scholar 

  59. von Ahsen N, Fichter M, Grupp C, et al. No influence of the MDR-1 C3435T polymorphism or a CYP3A4 promoter polymorphism (CYP3A4-V allele) on dose-adjusted cyclosporin A trough concentrations or rejection incidence in stable renal transplant recipients. Clin Chem 2001; 47: 1048–52

    Google Scholar 

  60. Min DI, Ellingrod V. C3435T mutation in exon 26 of the human MDR1 gene and cyclosporine pharmacokinetics in healthy subjects. Ther Drug Monit 2002; 24: 400–4

    PubMed  CAS  Google Scholar 

  61. Tanabe M, Ieiri I, Nagata N, et al. Expression of P-glycoprotein in human placenta: relation to genetic polymorphism of the multidrug resistance (MDR)-1 gene. J Pharmacol Exp Ther 2001; 297: 1137–43

    PubMed  CAS  Google Scholar 

  62. Cascorbi I, Gerloff T, Johne A, et al. Frequency of single nucleotide polymorphisms in the P-glycoprotein drug transporter MDR1 gene in white subjects. Clin Pharmacol Ther 2001; 69: 169–74

    PubMed  CAS  Google Scholar 

  63. Kalow W, Bertilsson L. Interethnic factors affecting drug response. Adv Drug Res 1994; 25: 1–53

    CAS  Google Scholar 

  64. Ameyaw M-M, Regateiro F, Li T, et al. MDR1 pharmacogenetics: frequency of the C3435T mutation in exon 26 is significantly influenced by ethnicity. Pharmacogenetics 2001; 11: 217–21

    PubMed  CAS  Google Scholar 

  65. Elmore JG, Moceri VM, Carter D, et al. Breast carcinoma tumor characteristics in black and white women. Cancer 1998; 83: 2509–15

    PubMed  CAS  Google Scholar 

  66. Ito S, Ieiri I, Tanabe M, et al. Polymorphism of the ABC transporter genes, MDR1, MRP1, and MRP2/cMOAT, in healthy Japanese subjects. Pharmacogenetics 2001; 11: 175–84

    PubMed  CAS  Google Scholar 

  67. Yamazaki M, Neway WE, Ohe T, et al. In vitro substrate identification studies for P-glycoprotein mediated transport: species difference and predictability of in vitro results. J Pharmacol Exp Ther 2001; 296: 723–35

    PubMed  CAS  Google Scholar 

  68. Gruol DJ, Vo QD, Zee MC. Profound differences in the transport of steroids by two mouse P-glycoproteins. Biochem Pharmacol 1999; 58: 1191–9

    PubMed  CAS  Google Scholar 

  69. Devault A, Gros P. Two members of mouse mdr gene family confer multidrug resistance with overlapping but distinct drug specificities. Mol Cell Biol 1990; 10: 1652–63

    PubMed  CAS  Google Scholar 

  70. Taylor JC, Ferry DR, Higgins CF, et al. The equilibrium and kinetic drug binding properties of the mouse P-gpla and P-gplb P-glycoproteins are similar. Br J Cancer 1999; 81: 783–9

    PubMed  CAS  Google Scholar 

  71. Tang-Wai DF, Kajiji S, DiCapua F, et al. Human (MDR1) and mouse (mdr1, mdr3) P-glycoproteins can be distinguished by their respective drug resistance profiles and sensitivity to modulators. Biochemistry 1995; 34: 32–9

    PubMed  CAS  Google Scholar 

  72. Croop JM, Raymond M, Haber D, et al. The three mouse multidrug resistance (mdr) genes are expressed in a tissue specific manner in normal mouse tissues. Mol Cell Biol 1989; 9: 1346–50

    PubMed  CAS  Google Scholar 

  73. Schuetz EG, Umbenhauer DR, Yasuda K, et al. Altered expression of hepatic cytochromes P-450 in mice deficient in one or more mdrl genes. Mol Pharm 2000; 57: 188–97

    CAS  Google Scholar 

  74. Aungst BJ. Novel formulation strategies for improving oral bioavailability of drug with poor membrane permeation or pre-systemic metabolism. J Pharm Sci 1993; 82: 979–87

    PubMed  CAS  Google Scholar 

  75. Ho NF, Park JY, Ni PF, et al. Advancing quantitative and mechanistic approaches in interfacing gastrointestinal drug absorption studies in animals and humans. In: Crouthamel W, Sarapu AC, editors. Animal models for oral drug delivery in man: in situ and in vivo approaches. Washington, DC: American Pharmaceutics Association, Academy of Pharmaceutical Sciences, 1983: 27–106

    Google Scholar 

  76. Pade V, Stavchansky S. Estimation of the relative contribution of the transcellular and paracellular pathway to the transport of passively absorbed drugs in the Caco-2 model. Pharm Res 1997; 14: 1210–5

    PubMed  CAS  Google Scholar 

  77. Creamer B. The turnover of the epithelium of small intestine. Br Med Bull 1967; 23: 226–30

    PubMed  CAS  Google Scholar 

  78. Fojo AT, Ueda K, Slamon DJ, et al. Expression of a multidrug resistance gene in human tumors and tissues. Proc Natl Acad Sci U S A 1987; 84: 265–9

    PubMed  CAS  Google Scholar 

  79. Fricker G, Drewe J, Huwyler J, et al. Relevance of P-glycoprotein for the enterai absorption of cyclosporine A: in vitro-in vivo correlation. Br J Pharmacol 1996; 118: 1841–7

    PubMed  CAS  Google Scholar 

  80. Nakayama A, Saitoh H, Oda M, et al. Region-dependent disappearance of vinblastine in rat small intestine and characterization of its P-glycoprotein-mediated efflux system. Eur J Pharm Sci 2000; 11: 317–24

    PubMed  CAS  Google Scholar 

  81. Lown KS, Mayo RR, Leichtman AB, et al. Role of intestinal P-glycoprotein (mdr1) in interpatient variation in the oral bioavailability of cyclosporine. Clin Pharmacol Ther 1997; 62: 248–60

    PubMed  CAS  Google Scholar 

  82. Masuda S, Uemoto S, Hashida T, et al. Effect of intestinal P-glycoprotein on daily tacrolimus trough level in a living-donor small bowel recipient. Clin Pharmacol Ther 2000; 68: 98–103

    PubMed  CAS  Google Scholar 

  83. Hunter J, Jepson MA, Tsuruo T, et al. Functional expression of P-glycoprotein in apical membranes of human intestinal Caco-2 cell layers: kinetics of vinblastine secretion and interaction with modulators. J Biol Chem 1993; 268: 14991–7

    PubMed  CAS  Google Scholar 

  84. Hunter J, Hirst BH, Simmons NL. Drug absorption limited by P-glycoprotein-mediated secretory drug transport in human intestinal epithelial Caco-2 cells. Pharm Res 1993; 10: 743–9

    PubMed  CAS  Google Scholar 

  85. Augustijins PF, Bradshaw TP, Gan LSL, et al. Evidence for a polarized efflux system in Caco-2 cells capable of modulating cyclosporine A transport. Biochem Biophys Res Commun 1993; 197: 360–5

    Google Scholar 

  86. Burton PS, Conradi RA, Hilgers AR, et al. Evidence for a polarized efflux system for peptides in the apical membrane of Caco-2 cells. Biochem Biophys Res Commun 1993; 190: 760–6

    PubMed  CAS  Google Scholar 

  87. Sparreboom A, van Asperen J, Mayer U, et al. Limited oral bioavailability and active epithelial excretion of paclitaxel (Taxol) caused by P-glycoprotein in the intestine. Proc Natl Acad Sci U S A 1997; 94: 2031–5

    PubMed  CAS  Google Scholar 

  88. Mayer U, Wagnaar E, Beijnen JH, et al. Substantial excretion of digoxin via the intestinal mucosa and prevention of long-term digoxin accumulation in the brain by the mdrl a P-glycoprotein. Br J Pharmacol 1996; 119: 1038–44

    PubMed  CAS  Google Scholar 

  89. Israili ZH, Dayton PG. Enhancement of xenobiotic elimination: role of intestinal excretion. Drug Metab Rev 1984; 15: 1123–59

    PubMed  CAS  Google Scholar 

  90. Meerum Terwgot JM, Malingre MM, Beijnen JH, et al. Co-administration of cyclosporin A enables oral therapy with paclitaxel. Clin Cancer Res 1999; 5: 3379–84

    Google Scholar 

  91. Malingre MM, Richel DJ, Beijinen JH, et al. Coadministration of cyclosporine strongly enhances the oral bioavailability of docetaxel. J Clin Oncol 2001; 19: 1160–6

    PubMed  CAS  Google Scholar 

  92. Bohme M, Buchler M, Muller M, et al. Differential inhibition by cyclosporines of primary-active ATP-dependent transporters in hepatocyte canalicular membrane. FEBS Lett 1993; 333: 193–6

    PubMed  CAS  Google Scholar 

  93. Stephens RH, O’Neill CA, Warhurst A, et al. Kinetic profiling of P-glycoprotein-mediated drug efflux in rat and human intestinal epithelia. J Pharmacol Exp Ther 2001; 296: 584–91

    PubMed  CAS  Google Scholar 

  94. Saeki T, Ueda K, Tanigawara Y, et al. Human P-glycoprotein transports cyclosporine A and FK506. J Biol Chem 1993; 268: 6077–80

    PubMed  CAS  Google Scholar 

  95. Wetterich U, Sphn-Langguth H, Mutschier E, et al. Evidence for intestinal secretion as an additional clearance pathway of talinolol enantiomers: concentration- and dose-dependent absorption in vitro and in vivo. Pharm Res 1996; 13: 514–22

    PubMed  CAS  Google Scholar 

  96. Ueda CT, Lemaire M, Gsell G, et al. Apparent dose dependent oral absorption of cyclosporine A in rats. Biopharm Drug Dispos 1984; 5: 141–51

    PubMed  CAS  Google Scholar 

  97. Hochman JH, Chiba M, Nishime J, et al. Influence of P-glycoprotein on the transport and metabolism of indinavir in Caco-2 cells expressing cytochrome P450 3A4. J Pharmacol Exp Ther 2000; 292: 310–8

    PubMed  CAS  Google Scholar 

  98. Lin JH. Role of pharmacokinetics in the discovery and development of indinavir. Adv Drug Deliv Rev 1999; 39: 33–49

    PubMed  CAS  Google Scholar 

  99. Chiou WL, Chung SM, Wu TC, et al. 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 2001; 39: 93–101

    PubMed  CAS  Google Scholar 

  100. Makhey VD, Guo A, Norris DA, et al. Characterization of the regional intestinal kinetics of drug efflux in rat and human intestine and in Caco-2 cells. Pharm Res 1998; 15: 1160–7

    PubMed  CAS  Google Scholar 

  101. Handschumacher RE. Immunosuppressive agents. In: Gilman AG, Palmer T, Nies AS, editors. Goodman and Gilman’s the pharmacological basis of therapeutics. 8th ed. New York (NY): McGraw-Hill Inc, 1990: 1264–76

    Google Scholar 

  102. Mouritsen OG, Jorgensen K, Honger T. Permeability of lipid bilayers near the phase transition. In: Disalvo EA, Simon SA, editors. Permeability and stability of lipid bilayers. Boca Raton (FL): CRC Press, 1995: 137–60

    Google Scholar 

  103. Eichler H-G, Muller M. Drug distribution: the forgotten relative in clinical pharmacokinetics. Clin Pharmacokinet 1998; 34: 95–9

    PubMed  CAS  Google Scholar 

  104. Kim RB. Transporters and drug disposition. Curr Opin Drug Discov Devel 2000; 3: 94–101

    PubMed  CAS  Google Scholar 

  105. Pardridge WM. Transport of protein-bound hormones into tissue in vivo. Endocr Rev 1981; 2: 103–23

    PubMed  CAS  Google Scholar 

  106. Rapoport SI. Transport in cells and tissues. In: Rapport SI, editor. Blood-brain barrier in physiology and medicine. New York (NY): Raven Press, 1976: 17–42

    Google Scholar 

  107. Chikhale EG, Ng K-Y, Burton PS, et al. Hydrogen bonding potential as a determinant of the in vitro and in situ blood-brain barrier permeability of peptides. Pharm Res 1994; 11: 412–9

    PubMed  CAS  Google Scholar 

  108. Levin VA. Relationship of octanol/water partition coefficient and molecular weight to rat brain capillary permeability. J Med Chem 1980; 23: 682–4

    PubMed  CAS  Google Scholar 

  109. Lin TH, Lin JH. Effects of protein binding and experimental disease states on brain uptake of benzodiazepines in rats. J Pharmacol Exp Ther 1990; 253: 45–50

    PubMed  CAS  Google Scholar 

  110. Thiebaut F, Tsuruo T, Hamada H, et al. 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 1989; 37: 159–64

    PubMed  CAS  Google Scholar 

  111. Cordon-Cardo C, O’Brien JP, Casals D, et al. Multidrug-resistance gene (P-glycoprotein) is expressed by endothelial cells at blood-brain barrier sites. Proc Natl Acad Sci U S A 1989; 86: 695–8

    PubMed  CAS  Google Scholar 

  112. Beaulieu E, Demeule M, Ghitescu L, et al. P-glycoprotein is strongly expressed in the luminal membranes of the endothe-lium of blood vessels in the brain. Biochem J 1997; 326: 539–44

    PubMed  CAS  Google Scholar 

  113. Barrand MA, Bennett GC, Taylor CJ, et al. Immunohistochemical localization in rat brain microvessels of transporters involved in solute and water movements across the blood-brain barrier [abstract]. IVth International Conference: Cerebral Vascular Biology, Blood-Brain Barrier; 2001 Apr 1–5; Cambridge, UK

  114. Matsuoka Y, Okazaki M, Kitamura Y, et al. Developmental expression of P-glycoprotein (multidrug resistance gene product) in the rat brain. J Neurobiol 1999; 39: 383–92

    PubMed  CAS  Google Scholar 

  115. Decleves X, Regina A, Laplanche J-L, et al. Functional expression of P-glycoprotein and multidrug resistance-associated protein (Mrp1) in primary cultures of rat astrocytes. J Neurosci Res 2000; 60: 594–601

    PubMed  CAS  Google Scholar 

  116. Pardridge WM, Golden PL, Kang Y-S, et al. Brain microvascular and astrocyte localization of P-glycoprotein. J Neurochem 1997; 68: 1278–85

    PubMed  CAS  Google Scholar 

  117. Golden PL, Pardridge WM. Brain microvascular P-glycoprotein and a revised model of multidrug resistance in brain. Cell Mol Neurobiol 2000; 20: 165–81

    PubMed  CAS  Google Scholar 

  118. de Lange ECM, de Bock G, Schinkel AH, et al. BBB transport and P-glycoprotein functionality using mdr1a (−/−) and wild-type mice: total brain versus microdialysis concentration profiles of rhodamine-123. Pharm Res 1998; 15: 1657–65

    PubMed  Google Scholar 

  119. Lee G, Schlichter L, Bendayan M, et al. Functional expression of P-glycoprotein in rat brain microglia. J Pharmacol Exp Ther 2001; 299: 204–12

    PubMed  CAS  Google Scholar 

  120. Chen C, Pollack GM. Altered disposition and antinociception of [D-penicillamine2,5]enkephalin in mdr1a-gene-deficient mice. J Pharmacol Exp Ther 1998; 287: 545–52

    PubMed  CAS  Google Scholar 

  121. Tsuji A, Terasaki T, Takabatake Y, et al. P-glycoprotein as the drug efflux pump in the primary cultured bovine brain capillary endothelial cells. Life Sci 1992; 51: 1427–37

    PubMed  CAS  Google Scholar 

  122. Tatsuta T, Naito M, Ohhara T, et al. Functional involvement of P-glycoprotein in blood-brain barrier. J Biol Chem 1992; 267: 20383–91

    PubMed  CAS  Google Scholar 

  123. Tsuji A, Tamai I, Sakata A, et al. Restricted transport of cyclosporine A across the blood-brain barrier by a multidrug transporter, P-glycoprotein. Biochem Pharmacol 1993; 46: 1096–9

    PubMed  CAS  Google Scholar 

  124. Shirai A, Naito M, Tatsuta T, et al. Transport of cyclosporin A across the brain capillary endothelial cell monolayer by P-glycoprotein. Biochim Biophys Acta 1994; 1222: 400–4

    PubMed  CAS  Google Scholar 

  125. Biegel D, Spencer DD, Pachter JS, et al. Isolation and culture of human brain microvessel endothelial cells for the study of blood-brain barrier properties in vitro. Brain Res 1995; 692: 183–9

    PubMed  CAS  Google Scholar 

  126. Hsing S, Gatmaitan Z, Arias IM. The function of Gp170, the multidrug-resistance gene product, in the brush border of rat intestinal mucosa. Gastroenterology 1992; 102: 879–85

    PubMed  CAS  Google Scholar 

  127. Kamimoto Y, Gatmaitan Z, Hsu J, et al. The function of Gp170, the multidrug resistance gene product, in rat liver canalicular membrane vesicles. J Biochem Chem 1989; 264: 11693–8

    CAS  Google Scholar 

  128. Ohnishi T, Tamai I, Sakanaka K, et al. In vivo and in vitro evidence for ATP-dependency of P-glycoprotein-mediated efflux of doxorubicin at the blood-brain barrier. Biochem Pharmacol 1995; 49: 1541–4

    PubMed  CAS  Google Scholar 

  129. Sakata A, Tamai I, Kawazu K, et al. In vivo evidence for ATP-dependent and P-glycoprotein-mediated transport of cyclosporin A at the blood-brain barrier. Biochem Pharmacol 1994; 48: 1989–92

    PubMed  CAS  Google Scholar 

  130. Schinkel AH, Wagenaar E, van Deemter L, et al. Absence of the mdrla P-glycoprotein in mice affects tissue distribution and pharmacokinetics of dexamethasone, digoxin, and cyclosporin A. J Clin Invest 1995; 96: 1698–705

    PubMed  CAS  Google Scholar 

  131. Schinkel AH, Mol CAAM, Wagenaar E, et al. Multidrug resistance and the role of P-glycoprotein knockout mice. Eur J Cancer 1995; 31A: 1295–8

    PubMed  CAS  Google Scholar 

  132. Yokogawa K, Takahashi M, Tamai I, et al. P-glycoprotein-dependent disposition kinetics of tacrolimus: studies in mdrla knockout mice. Pharm Res 1999; 16: 1213–8

    PubMed  CAS  Google Scholar 

  133. Smit JW, Huisman MT, van Teilingen O, et al. Absence or pharmacological blocking of placental P-glycoprotein profoundly increases fetal drug exposure. J Clin Invest 1999; 104: 1441–7

    PubMed  CAS  Google Scholar 

  134. Nakamura Y, Ikeda S, Furukawa T, et al. Function of P-glycoprotein expressed in placenta and mole. Biochem Biophys Res Commun 1997; 235: 849–53

    PubMed  CAS  Google Scholar 

  135. Ushigome F, Takanaga H, Matsuo H, et al. Human placental transport of vinblastine, vincristine, digoxin and progesterone: contribution of P-glycoprotein. Eur J Pharmacol 2000; 408: 1–10

    PubMed  CAS  Google Scholar 

  136. Krishna DR, Klotz U. Extrahepatic metabolism of drugs in humans. Clin Pharmacokinet 1994; 26: 144–60

    PubMed  CAS  Google Scholar 

  137. Debri K, Boobis AR, Davis DS, et al. Distribution and induction of CYP3A1 and CYP3A2 in rat liver and extrahepatic tissues. Biochem Pharmacol 1995; 50: 2047–56

    PubMed  CAS  Google Scholar 

  138. Watkins PB, Murray SA, Thomas PE, et al. Distribution of cytochromes P-450, cytochrome b5, and NADPH-cytochrome P-450 reductase in an entire human liver. Biochem Pharmacol 1990; 39: 471–6

    PubMed  CAS  Google Scholar 

  139. Murray GI, Barnes TS, Sewell HF, et al. The immunochemical localisation and distribution of cytochrome P-450 in normal hepatic and extrahepatic tissues with a monoclonal antibody to human cytochrome P-450. Br J Clin Pharmacol 1988; 25: 465–75

    PubMed  CAS  Google Scholar 

  140. Thummel KE, Kunze KL, Shen DD. Enzyme-catalyzed processes of first-pass hepatic and intestinal drug extraction. Adv Drug Deliv Rev 1997; 27: 99–127

    PubMed  CAS  Google Scholar 

  141. Hochman JH, Chiba M, Yamazaki M, et al. P-glycoprotein-mediated efflux of indinavir metabolites in Caco-2 cells expressing cytochrome P450 3A4. J Pharmacol Exp Ther 2001; 298: 323–30

    PubMed  CAS  Google Scholar 

  142. Gan L-SL, Moseley MA, Khosla B, et al. CYP3A-like cytochrome P450-mediated metabolism and polarized efflux of cyclosporin A in Caco-2 cells. Drug Metab Dispos 1996; 24: 344–9

    PubMed  CAS  Google Scholar 

  143. Lin JH, Chiba M, Chen I-W, et al. Effect of dexamethasone on the intestinal first-pass metabolism of indinavir in rats: evidence of cytochrome P-450 3 A and P-glycoprotein induction. Drug Metab Dispos 1999; 27: 1187–93

    PubMed  CAS  Google Scholar 

  144. Lin JH, Chiba M, Baillie TA. Is the role of the small intestine in first-pass metabolism overemphasized?. Pharmacol Rev 1999; 51: 135–57

    PubMed  CAS  Google Scholar 

  145. Meijer DKF, Smit JW, Muller M. Hepatobiliary elimination of cationic drugs: the role of P-glycoproteins and other ATP-dependent transporters. Adv Drug Deliv Rev 1997; 25: 159–200

    CAS  Google Scholar 

  146. Koepsell H, Gorboulev V, Arndt P. Molecular pharmacology of organic cation transporters in kidney. J Membr Biol 1999; 167: 103–17

    PubMed  CAS  Google Scholar 

  147. Watanabe T, Miyauchi S, Sawada Y, et al. Kinetic analysis of hepatobiliary transport of vincristine in perfused rat liver: possible roles of P-glycoprotein in biliary excretion of vincristine. J Hepatol 1992; 16: 77–88

    PubMed  CAS  Google Scholar 

  148. Ballet F, Vrignaud P, Robert J, et al. Hepatic extraction, metabolism and biliary excretion of doxorubicin in the isolated perfused rat liver. Cancer Chemother Pharmacol 1987; 19: 240–5

    PubMed  CAS  Google Scholar 

  149. Kawahara M, Sakata A, Miyashita T, et al. Physiologically based pharmacokinetics of digoxin in mdrla knockout mice. J Pharm Sci 1999; 88: 1281–7

    PubMed  CAS  Google Scholar 

  150. van Asperen J, van Teilingen O, Beijnen JH. The role of mdrla P-glycoprotein in the biliary and intestinal secretion of doxorubicin and vinblastine in mice. Drug Metab Dispos 2000; 28: 264–7

    PubMed  Google Scholar 

  151. Smit JW, Schinkel AH, Muller M, et al. Contribution of the murine mdrla P-glycoprotein to hepatobiliary and intestinal elimination of cationic drugs as measured in mice with an mdrla gene disruption. Hepatology 1998; 27: 1056–63

    PubMed  CAS  Google Scholar 

  152. Smit JW, Schinkel AH, Weert B, et al. Hepatobiliary and intestinal clearance of amphiphilic cationic drugs in mice in which both mdrla and mdr1b genes have been disrupted. Br J Pharmacol 1998; 124: 416–24

    PubMed  CAS  Google Scholar 

  153. Okamura N, Hirai M, Tanigawara Y, et al. Digoxin-cyclosporin A interaction: modulation of the multidrug transporter P-glycoprotein in the kidney. J Pharmacol Exp Ther 1993; 266: 1614–9

    PubMed  CAS  Google Scholar 

  154. Tanigawara Y, Okamura N, Hirai M, et al. Transport of digoxin by human P-glycoprotein expressed in a porcine kidney epithelial cell line (LLC-PK1). J Pharmacol Exp Ther 1992; 263: 840–5

    PubMed  CAS  Google Scholar 

  155. Horio M, Chin K-V, Currier SJ, et al. Transepithelial transport of drugs by the multidrug transporter in cultured Madin-Darby canine kidney cell epithelia. J Biol Chem 1989; 264: 14880–4

    PubMed  CAS  Google Scholar 

  156. Hori R, Okamura N, Aiba T, et al. Role of P-glycoprotein in renal tubular secretion of digoxin in the isolated perfused rat kidney. J Pharmacol Exp Ther 1993; 266: 1620–5

    PubMed  CAS  Google Scholar 

  157. De Lannoy IAM, Koren G, Klein J, et al. Cyclosporin and quinidine inhibition of renal digoxin excretion: evidence for luminal secretion of digoxin. Am J Physiol 1992; 263: F613–22

    PubMed  Google Scholar 

  158. van Asperen J, van Tellinge O, Tijssen F, et al. Increased accumulation of doxorubicin and doxorubicinol in cardiac tissue of mice lacking mdrla P-glycoprotein. Br J Cancer 1999; 79: 108–13

    PubMed  Google Scholar 

  159. Lin JH, Lu AYH. Inhibition and induction of cytochrome P450 and the clinical implications. Clin Pharmacokinet 1998; 35: 361–90

    PubMed  CAS  Google Scholar 

  160. Ronis MJJ, Ingelman-Sundberg M. Induction of human drugmetabolizing enzymes: mechanism and implications. In: Woolf TF, editor. Handbook of drug metabolism. New York (NY): Marcel Dekker Inc, 1999: 239–62

    Google Scholar 

  161. Lazarou J, Pomeraanz BH, Corey PN. Incidence of adverse drug reactions in hospitalized patients: a meta-analysis of prospective studies. JAMA 1998; 279: 1200–5

    PubMed  CAS  Google Scholar 

  162. Duchateau AMJA. Posicor: veni, vidi, foetsie. Pharm Weekbl 1998; 133: 1294–5

    Google Scholar 

  163. Ford JM. Experimental reversal of P-glycoprotein-mediated multidrug resistance by pharmacological chemosensitisers. Eur J Cancer 1996; 32A: 991–1001

    PubMed  CAS  Google Scholar 

  164. Tamai I, Safa AR. Azidopine noncompetitively interacts with vinblastine and cyclosporin A binding to P-glycoprotein in multidrug resistant cells. J Biol Chem 1991; 266: 16796–800

    PubMed  CAS  Google Scholar 

  165. Ramachandra M, Ambudkar SV, Chen D, et al. Human P-glycoprotein exhibits reduced affinity for substrates during a catalytic transition state. Biochemistry 1998; 37: 5010–9

    PubMed  CAS  Google Scholar 

  166. Senior AE, Al-Shawi MK, Urbatsch IL. The catalytic cycle of P-glycoprotein. FEBS Lett 1995; 377: 285–9

    PubMed  CAS  Google Scholar 

  167. Ayesh S, Shao Y-M, Stein WD. Co-operative, competitive and non-competitive interactions between modulators of P-glycoprotein. Biochim Biophys Acta 1996; 1316: 8–18

    PubMed  Google Scholar 

  168. Tamai I, Safa AR. Competitive interaction of cyclosporins with the vinca alkaloid-binding site of P-glycoprotein in multidrug resistant cells. J Biol Chem 1990; 265: 16509–13

    PubMed  CAS  Google Scholar 

  169. Callaghan R, Riordan JR. Synthetic and nature opiates interact with P-glycoprotein in multidrug resistant cells. J Biol Chem 1993; 268: 16059–64

    PubMed  CAS  Google Scholar 

  170. Litman T, Zeuthen T, Skovsgaard T, et al. Competitive, non-competitive and cooperative interactions between substrates of P-glycoprotein as measured by its ATPase activity. Biochim Biophys Acta 1997; 1361: 169–76

    PubMed  CAS  Google Scholar 

  171. Pascaud C, Garrigos M, Orlowski S. Multidrug resistance transporter P-glycoprotein has distinct but interacting binding sites for cytotoxic drugs and reversing agents. Biochem J 1998; 333: 351–8

    PubMed  CAS  Google Scholar 

  172. Critchfield JW, Welsh CJ, Phang JM, et al. Modulation of adriamycin accumulation and efflux by flavonoids in HCT-15 colon cells. Biochem Pharmacol 1994; 48: 1437–45

    PubMed  CAS  Google Scholar 

  173. Shapiro AB, Ling V. Positively cooperative sites for drug transport by P-glycoprotein with distinct drug specificities. Eur J Biochem 1997; 250: 130–7

    PubMed  CAS  Google Scholar 

  174. Houston JB, Kenworthy KE. In vitro-in vivo scaling of CYP kinetic data not consistent with the classical Michaelis-Menten model. Drug Metab Dispos 2000; 28: 246–54

    PubMed  CAS  Google Scholar 

  175. Wang RW, Newton DJ, Liu N, et al. Human cytochrome P450 3A4; in vitro drug-drug interaction patterns are substrate-dependent. Drug Metab Dispos 2000; 28: 360–6

    PubMed  CAS  Google Scholar 

  176. Shou M, Mei Q, Ettore MW, et al. Sigmoidal kinetic model for two co-operative substrate-binding sites in a cytochrome P450 3A4 active site: an example of the metabolism of diazepam and its derivatives. Biochem J 1999; 340: 845–53

    PubMed  CAS  Google Scholar 

  177. Wandel C, Kim RB, Kajiji S, et al. P-glycoprotein and cytochrome P-450 3A inhibition: dissociation of inhibitory potencies. Cancer Res 1999; 59: 3944–8

    PubMed  CAS  Google Scholar 

  178. Choo EF, Leake B, Wandel C, et al. Pharmacological inhibition of P-glycoprotein transport enhances the distribution of HIV-1 protease inhibitors into brain and testes. Drug Metab Dispos 2000; 28: 655–60

    PubMed  CAS  Google Scholar 

  179. Polli JW, Jarrett JL, Studenberg SD, et al. Role of P-glycoprotein on the CNS disposition of amprenavir (141W94), an HIV protease inhibitor. Pharm Res 1999; 16: 1206–12

    PubMed  CAS  Google Scholar 

  180. Mayer U, Wagenaar E, Dorobek B, et al. Full blockade of intestinal P-glycoprotein and extensive inhibition of blood-brain barrier P-glycoprotein by oral treatment of mice with PSC833. J Clin Invest 1997; 100: 2430–6

    PubMed  CAS  Google Scholar 

  181. Sadeque AJ, Wandel C, He H, et al. Increased drug delivery to the brain by P-glycoprotein inhibition. Clin Pharmacol Ther 2000; 68: 231–7

    PubMed  CAS  Google Scholar 

  182. Verschraagen M, Koks CHW, Schellens JHM, et al. P-glycoprotein system as a determinant of drug interactions: the case of digoxin-verapamil. Pharmacol Res 1999; 40: 301–6

    PubMed  CAS  Google Scholar 

  183. Bussey HI. The influence of quinidine and other agents on digitalis glycosides. Am Heart J 1982; 104: 289–302

    PubMed  CAS  Google Scholar 

  184. Mordel A, Halkin H, Zulty L, et al. Quinidine enhances digitalis toxicity at therapeutic serum digoxin levels. Clin Pharmacol Ther 1993; 53: 457–62

    PubMed  CAS  Google Scholar 

  185. Pedersen KE. Digoxin interaction: the influence of quinidine and verapamil on pharmacokinetics and receptor binding of digitalis glycosides. Acta Med Scand 1985; 697: 11–40

    Google Scholar 

  186. Hinderling PH, Hartmann D. Pharmacokinetics of digoxin and main metabolites/derivatives in healthy humans. Ther Drug Monit 1991; 13: 381–401

    PubMed  CAS  Google Scholar 

  187. Sababi M, Borga O, Hultkvist-Bengtsson U. The role of P-glycoprotein in limiting intestinal regional absorption of digoxin in rats. Eur J Pharm Sci 2001; 14: 21–7

    PubMed  CAS  Google Scholar 

  188. Su FG, Huang JD. Inhibition of the intestinal digoxin absorption and exsorption by quinidine. Drug Metab Dispos 1996; 24: 142–7

    PubMed  CAS  Google Scholar 

  189. Tsuruo T, Lida H, Tsukagoshi S, et al. Overcoming of vincristine resistance in P388 leukemia in vivo and in vitro through enhanced cytotoxicity of vincristine and vinblastine by verapamil. Cancer Res 1981; 41: 1967–72

    PubMed  CAS  Google Scholar 

  190. Advani R, Fisher GA, Lum BL, et al. A phase I trial of doxorubicin, paclitaxel, and valspodar (PSC833), a modulator of multidrug resistance. Clin Cancer Res 2001; 7: 1221–9

    PubMed  CAS  Google Scholar 

  191. Sparreboom A, St Planting A, Jewell RC, et al. Clinical pharmacokinetics of doxorubicin in combination with GF120918, a potent inhibitor of MDR1 P-glycoprotein. Anticancer Drugs 1999; 10: 719–28

    PubMed  CAS  Google Scholar 

  192. van Zuylen L, Nooter K, Sparreboom A, et al. Development of multidrug resistance convertors: sense or nonsense?. Invest New Drugs 2000; 18: 205–20

    PubMed  Google Scholar 

  193. Johannessen A, Rendtorff C, Poulsen S. Digoxin intoxication induced by verapamil in an uremic patient. Clin Nephrol 1985; 24: 158–9

    PubMed  CAS  Google Scholar 

  194. Klein HO, Lang R, Weiss E, et al. The influence of verapamil on serum digoxin concentration. Circulation 1982; 65: 998–1003

    PubMed  CAS  Google Scholar 

  195. Fardel O, Lecureur V, Corlu A, et al. P-glycoprotein induction in rat liver epithelial cells in response to acute 3-methycholanthrene treatment. Biochem Pharmacol 1996; 51: 1427–36

    PubMed  CAS  Google Scholar 

  196. Chin KV, Chauhan SS, Pastan I, et al. Regulation of mdr RNA levels in response to cytotoxic drugs in rodent cells. Cell Growth Differ 1990; 1: 361–5

    PubMed  CAS  Google Scholar 

  197. LeCluyse EL. Pregnane X receptor: molecular basis for species differences in CYP3A induction by xenobiotics. Chem Biol Interact 2001; 134: 283–9

    PubMed  CAS  Google Scholar 

  198. Fardel O, Lecureur V, Guillouzo A. Regulation by dexamethasone of P-glycoprotein expression in cultured rat hepatocytes. FEBS Lett 1993; 327: 189–93

    PubMed  CAS  Google Scholar 

  199. Zhao JY, Ikeguchi M, Eckersberg T, et al. Modulation of multi-drug resistance gene expression by dexamethasone in cultured hepatoma cells. Endocrinology 1993; 133: 521–8

    PubMed  CAS  Google Scholar 

  200. Salphati L, Benet LZ. Modulation of P-glycoprotein expression by cytochrome P450 3A inducers in male and female rat livers. Biochem Pharmacol 1998; 55: 387–95

    PubMed  CAS  Google Scholar 

  201. Liu J, Brunner LJ. Chronic cyclosporine administration induces renal P-glycoprotein in rats. Eur J Pharmacol 2001; 418: 127–32

    PubMed  CAS  Google Scholar 

  202. Jette L, Beaulieu E, Leclerc J-M, et al. Cyclosporin A treatment induces overexpression of P-glycoprotein in the kidney and other tissues. Am J Physiol 1996; 270: F756–65

    PubMed  CAS  Google Scholar 

  203. Lee CH. Induction of P-glycoprotein mRNA transcripts by cycloheximide in animal tissues: evidence that class I Pgp is transcriptionally regulated whereas class II Pgp is post-transcriptionally regulated. Mol Cell Biochem 2001; 216: 103–10

    PubMed  CAS  Google Scholar 

  204. Durr D, Stieger B, Kullak-Ublick GA, et al. St. John’s Wort induces intestinal P-glycoprotein/MDR1 and intestinal and hepatic CYP3A4. Clin Pharmacol Ther 2000; 68: 598–604

    PubMed  CAS  Google Scholar 

  205. Schuetz EG, Beck WT, Schuetz JD. Modulators and substrates of P-glycoprotein and cytochrome P450 3 A coordinately up-regulated these proteins in human colon carcinoma cells. Mol Pharmacol 1996; 49: 311–8

    PubMed  CAS  Google Scholar 

  206. Pichard L, Fabre I, Daujat M, et al. Effect of corticosteroids on the expression of cytochromes P450 and on cyclosporin A oxidase activity in primary cultures human hepatocytes. Mol Pharmacol 1992; 41: 1047–55

    PubMed  CAS  Google Scholar 

  207. Wacher VJ, Wu C-Y, Benet LZ. Overlapping substrate specificities and tissue distribution of cytochrome P450 3A and P-glycoprotein: implications for drug delivery and activity in cancer chemotherapy. Mol Carcinog 1995; 13: 129–34

    PubMed  CAS  Google Scholar 

  208. Callen DF, Baker E, Simmers RN, et al. Localization of the human multidrug resistance gene, MDR1, to 7q21.1. Hum Genet 1987; 77: 142–4

    PubMed  CAS  Google Scholar 

  209. Inoue K, Inazawa J, Nakagawa H, et al. Assignment of the human cytochrome P450 nifedipine oxidase gene (CYP3A4) to chromosome 7 at band q22.1 by fluorescence in situ hybridization. Jpn J Hum Genet 1992; 37: 133–8

    PubMed  CAS  Google Scholar 

  210. Quattrochi LC, Guzelian PS. CYP3A regulation: from pharmacology to nuclear receptors. Drug Metab Dispos 2001; 29: 615–22

    PubMed  CAS  Google Scholar 

  211. Jones SA, Moore LB, Shenk JL, et al. The pregnane X receptor: a promiscuous xenobiotic receptor that has diverged during evolution. Mol Endocrinol 2000; 14: 27–39

    PubMed  CAS  Google Scholar 

  212. Blumberg B, Sabbagh W Jr, Juguilon H, et al. SXR, a novel steroid and xenobiotic—sensing nuclear receptor. Genes Dev 1998; 12: 3195–205

    PubMed  CAS  Google Scholar 

  213. 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: 7500–2

    PubMed  CAS  Google Scholar 

  214. Synold TW, Dussault I, Forman BM. The orphan nuclear receptor SXR coordinately regulates drug metabolism and efflux. Nature Med 2001; 7: 584–90

    PubMed  CAS  Google Scholar 

  215. Geick A, Eichelbaum M, Burk O. Nuclear receptor response elements mediate induction of intestinal MDR1 by rifampin. J Biol Chem 2001; 276: 14581–7

    PubMed  CAS  Google Scholar 

  216. Masuyama H, Hiramatsu Y, Mizutani Y, et al. The expression of pregnane X receptor and its target gene, cytochrome P450 3A1 in prenatal mouse. Mol Cell Endocrinol 2001; 172: 47–56

    PubMed  CAS  Google Scholar 

  217. Greiner B, Eichelbaum M, Fritz P, et al. The role of intestinal P-glycoprotein in the interaction of digoxin and rifampin. J Clin Invest 1999; 104: 147–53

    PubMed  CAS  Google Scholar 

  218. Hamman MA, Bruce MA, Haehner-Daniels BD, et al. The effect of rifampin administration on the disposition of fexofenadine. Clin Pharmacol Ther 2001; 69: 114–21

    PubMed  CAS  Google Scholar 

  219. Lippert C, Ling J, Brown P, et al. Mass balance and pharmacokinetics of MDL16,455A in healthy male volunteers [abstract]. Pharm Res 1999; 12: S390

    Google Scholar 

  220. Cvetkovic M, Leake B, Fromm MF, et al. OATP and P-glycoprotein transporters mediate the cellular uptake and excretion of fexofenadine. Drug Metab Dispos 1999; 27: 866–71

    PubMed  CAS  Google Scholar 

  221. Hebert MF, Roberts JP, Prueksaritanont T, et al. Bioavailability of cyclosporine with concomitant rifampin administration is markedly less than predicted by hepatic enzyme induction. Clin Pharmacol Ther 1992; 52: 453–7

    PubMed  CAS  Google Scholar 

  222. Wacher VJ, Silverman JA, Zhang Y, et al. Role of P-glycoprotein and cytochrome P450 3A in limiting oral absorption of peptides and peptidomimetics. J Pharm Sci 1998; 87: 1322–30

    PubMed  CAS  Google Scholar 

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    Jiunn H. Lin & Masayo Yamazaki

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Lin, J.H., Yamazaki, M. Role of P-Glycoprotein in Pharmacokinetics. Clin Pharmacokinet 42, 59–98 (2003). https://doi.org/10.2165/00003088-200342010-00003

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