Role of transport proteins in drug absorption, distribution and excretion

References

• ABEL, S., BEAUMONT, K. C., CRESPI, C. L., Fox, L., HYLAND, R., JONES, B. C., MUIRHEAD, G. J., SMITH, D. A., VENN, R. F. and WALKER, D. K., 2001, A potential role for P-glycoprotein in the non-proportional pharmacokinetics of UK-343,664 in man. Xenobiotica, 31, 595–606.
   Web of Science ®Google Scholar
• ABEL, S., NicitoLs, D. J., BREARLEY, C. J. and EVE, M. D., 2000, Effect of cirnetidine and ranitidine on pharmacokinetics and pharmacodynamics of a single dose of dofetilide. British journal of Clinical Pharmacology, 49, 64–71.
   PubMed Web of Science ®Google Scholar
• ANGELIN, B., ARVIDSSON, A., DAHLQVIST, R., HEDMAN, A. and SCHENK-GUSTAPSSON, K., 1987, Quinidine reduces biliary clearance of digoxin in man. European journal of Clinical Investigation, 17, 262–265.
   Google Scholar
• AQUILANTE, C. L., LETRENT, S. P., POLLACK, G. M. and BROUWER, K. L. R., 2000, Increased brain P-glycoprotein in morphine tolerant rats. Life Sciences, 66, PL47–51.
   PubMed Web of Science ®Google Scholar
• BEAUMONT, K., HARPER, A., SMITH, D. A. and BENNETT, J., 2000, The role of P-glycoprotein in determining the oral absorption and clearance of the NK2 antagonist, UK-224,671. European Journal of Pharmaceutical Sciences, 12, 41–50.
   PubMed Web of Science ®Google Scholar
• BEGLEY, D. J., 1992, The interaction of some centrally active drugs with the blood—brain barrier and circumventricular organs. Progress in Brain Research, 91, 1 63–169.
   PubMedGoogle Scholar
• BELZ, G. G., DOERING, W., MUNKES, R. and MArrnEws, J., 1983, Interaction between digoxin and calcium antagonists and anti-arrhythmic drugs. Clinical Pharmacology and Therapeutics, 33, 410–417.
   PubMed Web of Science ®Google Scholar
• BENET, L. Z., Wu, C.Y., HEBERT, M. F. and WACHER, V. J., 1996, Intestinal drug metabolism and antitransport processes: a potential paradigm shift in oral drug delivery. Journal of Controlled Release, 39, 139–143.
   Web of Science ®Google Scholar
• BERGWERK, A. J., SHI, X., FORD, A. C., KANAI, N., JACQUEMIN, E., BURR, R. D., BAI, S., NOVIKO, P. M., STIEGER, B., MEIER, P. J., SCHUSTER, V. L. and WOLKO, A. W., 1996, Immunologic distribution of an organic anion transport protein in rat liver and kidney. American journal of Physiology, 271, G231—G238.
   Google Scholar
• BORST, P., EVERS, R., KooL, M. and WHNHOLDS, J., 1999, The multidrug resistance protein family. Biochimica et Biophyska Acta, 1461, 347–357.
   PubMed Web of Science ®Google Scholar
• BORST, P. and SCHINKEL, A. H., 1996, What have you learnt thus far from mice with disrupted P-glycoprotein genes? European Journal of Cancer, 32A, 985–990.
   Google Scholar
• CEFALU, W. T. and PARDRIDGE, W. M, 1985, Restrictive transport of a lipid soluble peptide (cyclosporin) through the blood—brain barrier. Journal of Neurochemistry, 45, 1954–1956.
   PubMed Web of Science ®Google Scholar
• CHOO, E. F., LEAKE, B., WANDEL, C., IMAMURA, H., WOOD, A. J. J., WILKINSON, G. R. and KIM, R. B., 2000, Pharmacological inhibition of P-glycoprotein transport enhances the distribution of HIV-1 protease inhibitors into brain and testes. Drug Metabolism and Disposition, 28, 655–660.
   Google Scholar
• CHRISTIAN, C. D., MEREDITH, C. G. and SPEEG, K. V., 1984, Cimetidine inhibits renal procainamide clearance. Clinical Pharmacology and Therapeutics, 36, 221–227.
   PubMed Web of Science ®Google Scholar
• Citu, X. Y., KATO, Y. and SUGIYAMA, Y., 1997, Multiplicity of biliary excretion mechanisms for irinotecan, CPT-11, and its metabolites in rat. Cancer Research, 57, 1934-1 938.
   Google Scholar
• CIHLAR, T., LIN, D. C., PRITCHARD, J. B., FULLER, M. D., MENDEL, D. B. and SWEET, D. H., 1999, The antiviral nucleotide analogs cidofovir and adefovir are novel substrates for human and rat renal organic anion transporter 1. Molecular Pharmacology, 56, 570–580.
   PubMed Web of Science ®Google Scholar
• CORDON-CARDO, C., OIRIEN, J. P., CASALS, D., RITTMAN-GRAVER, L., BEIDLER, J. L., MELAMED, M. R. and BERTINO, J. R., 1989, Multidrug resistance gene P-glycoprotein is expressed by endothelial cells at blood—brain barrier sites, Proceedings of the National Academy of Sciences, USA, 86, 695–698.
   Google Scholar
• CUNDY, K. C., 1999, Clinical pharmacokinetics of the antiviral nucleotide analogues cidofovir and adefovir. Clinical Pharmacokinetics, 36, 127-1 43.
   Google Scholar
• Cul, Y., KONIG, J., LEIER, I., BUCHHOLZ, U. and KEPPLER, D., 2000, Hepatic uptake of bilirubin and its conjugates by the human organic anion-transporting polypeptide SLC21A6. Journal of Biological Chemistry (in press).
   Google Scholar
• CVETKOVIC, M., LEAKE, B., FROMM, M. F., WILKINSON, G. R. and Kim, R. B., 1999, OATP and P-glycoprotein transporters mediate the cellular uptake and excretion of fexofenadine. Drug Metabolism and Disposition, 27, 866–871.
   PubMed Web of Science ®Google Scholar
• DAHLQVIST, R., EJVINSSON, G. and SCHENK-GUSTAFSSON, K., 1980, Effect of quinidine on plasma concentration and renal clearance of digoxin. A clinically important drug interaction. British Journal of Clinical Pharmacology, 9, 413–418.
   Google Scholar
• DANTZLER, W. H. and WRIGHT, S. H., 1997, Renal tubular secretion of organic anions. Advanced Drug Delivery Reviews, 25, 21 7–230.
   Google Scholar
• DE MIRANDA, P., GOOD, S. S., YARCHOAN, R., THOMAS, R. V., BLUM, M. R. and MYERS, C. E., 1989, Alteration of zidovudine pharmacokinetics by probenecid in patients with AIDS and AIDS-related complex. Clinical Pharmacology and Therapeutics, 46, 494–500.
   PubMed Web of Science ®Google Scholar
• DRESSER, G. K., SPENCE, J. D. and BAILEY, D. G., 2000, Pharmacokinetic-pharmacodynamic consequences and clinical relevance of cytochrome P450 3A4 inhibition. Clinical Pharmacokinetics, 38, 41–57.
   PubMed Web of Science ®Google Scholar
• DUBIN, I. N. and JOHNSON, F. B., 1954, Chronic idiopathic jaundice with unidentified pigment in liver cells: a new clinicopathologic entity with report of 12 cases. Medicine, 33, 155–179.
   PubMed Web of Science ®Google Scholar
• DURR, D., STEIGER, B., KULLAK-UBLICK, G. A., RENTSCH, K. M., STEINERT, H. C., MEIER, P. J. and FATTINGER, K., 2000, St John's Wort induces intestinal P-glycoprotein/MDR1 and intestinal and hepatic CYP3A4. Clinical Pharmacology and Therapeutics, 68, 598–604.
   Google Scholar
• ECKHARDT, U., STUBER, W., DICKNEITE, G., REERS, M. and PETZINGER, E., 1996, First-pass elimination of a peptidomimetic thrombin inhibitor is due to carrier-mediated uptake by the liver. Biochemical Pharmacology, 52, 65–96.
   PubMed Web of Science ®Google Scholar
• FENSTER, P. E., WHITE, N. W. and HANSON, C. D., 1985, Pharmacokinetic evaluation of the digoxin—amiodarone interaction. Journal of American College Cardiology, 5, 1 08–112.
   Web of Science ®Google Scholar
• FOJO, A. T., UEDA, K., SLAMON, D. J., POPLACK, D. G., GOTTESMAN, M. M. and PASTAN, I., 1987, Expression of a multidrug resistance gene in human tumours and tissues. Proceedings of National Academy of Sciences, USA, 84, 265–269.
   PubMed Web of Science ®Google Scholar
• FRICKER, G., DREWE, J., HUWYLER, J., GUTMANN, H. and BEGLINGER, C., 1996, Relevance of p-glycoprotein for the enteral absorption of cyclosporin A: in vitro—in vivo correlation. British Journal of Pharmacology, 118, 1841–1847.
   Web of Science ®Google Scholar
• FROMM, M. F., KAUFMANN, H. M., FRITZ, P., BURR, O., KROEMER, H. K., WARZOK, R. W., EICHELBACM, M., SIEGMUND, W. and SCHRENK, D., 2000, The effect of rifampicin treatment on intestinal expression of human MRP transporters. American Journal of Pathology, 157, 1575-1 580.
   Google Scholar
• FROMM, M. F., Km, R. B., STEIN, C. M., WILKINSON, G. R. and RODEN, D. M., 1999, Inhibition of P-glycoprotein-mediated drug transport: a unifying mechanism to explain the interaction between digoxin and quinidine. Circulation, 99, 552–557.
   PubMed Web of Science ®Google Scholar
• GAN, L. S. L., MOSELEY, G. M., KHOSLA, B., ÄUGUSTIJNS, P. F., BRADSHAW, T. P., HENDREN, R. W. and THAKKER, D. R., 1996, CYP3A-like cytochrome P450-mediated metabolism and polarised efflux of cyclosporin A in Caco-2 cells. Drug Metabolism and Disposition, 24, 344–349.
   Google Scholar
• GANT, T. W., °CONNOR, C. K., CORBITT, R., THORGEIRSSON, U. and THORGEIRSSON, S. S., 1995, In vivo induction of liver P-glycoprotein expression by xenobiotics in monkeys. Toxicology and Applied Pharmacology, 133, 269–276.
   Google Scholar
• GAO, B., STEIGER, B., NOE, B., FRITSCHY, J. M. and MEIJER, P. J., 1999, Localisation of the organic anion transporting polypeptide 2 (Oatp2) in capillary endothelium and choroid plexus epithelium of rat brain. Journal of Histochemistry and Cytochemisby, 47, 1255–1263.
   PubMed Web of Science ®Google Scholar
• GARDNER, I. B., FENNER, K. and MORGAN, P., 2000, Using the model compound pravastatin to understand in vitro—in vivo correlations for transport proteins. Drug Metabolism Reviews, 32 (suppl. 1), 55.
   Google Scholar
• GARDNER, I. B., WALKER, D. K., LENNARD, M. S., SMITH, D. A. and TUCKER, G. T., 1995, Comparison of the disposition of two novel combined thromboxane synthase inhibitors/thromboxane A2 receptor antagonists in the isolated perfused rat liver. Xenobiotica, 25, 185–197.
   PubMed Web of Science ®Google Scholar
• GOLDSTEIN, G. W. and BETZ, A. L., 1986, The blood—brain barrier. Science American, 255, 70–79.
   Web of Science ®Google Scholar
• GRAMATTE, T. and °ERTEL, R., 1999, Intestinal secretion of intravenous talinolol is inhibited by luminal R-verapamil. Clinical Pharmacology and Therapeutics, 66, 239–245.
   Google Scholar
• GRAMATTE, T., °ERTEL, R., TERHAAG, B. and KIRCH, W., 1996, Direct demonstration of small intestinal secretion and site-dependent absorption of the /3-blocker talinolol in humans. Clinical Pharmacology and Therapeutics, 59, 541–549.
   Google Scholar
• GREINER, B., EICHELBAUM, M., FRITZ, P., KREICHGAUER, H. P., VON RICHTER, O., ZUNDLER, J. and KROEMER, H. K., 1999, The role of intestinal P-glycoprotein in the interaction of digoxin and rifampicin. Journal of Clinical Investigation, 104, 147-1 53.
   Google Scholar
• GUTMANN, H., FRICKER, G., DREWE, J., TOEROEK, M. and MILLER, D. S., 1999, Interactions of HIV protease inhibitors with ATP-dependent drug export proteins. Molecular Pharmacology, 56, 383–389.
   PubMed Web of Science ®Google Scholar
• HAGENBUCH, B., 1997, Molecular properties of hepatic uptake systems for bile acids and organic anions. Journal of Membrane Biology, 160, 1–8.
   PubMed Web of Science ®Google Scholar
• HEBERT, M. F., 1997, Contributions of hepatic and intestinal metabolism and P-glycoprotein to cyclosporin and tacrolimus oral drug delivery. Advanced Drug Delivery Reviews, 27, 201–214.
   PubMed Web of Science ®Google Scholar
• HENDRIKSE, N. H., SCHINKEL, A. H., DE VRIES, E. G. E., FLUKS, E., VAN DER GRAAF, W. T. A., WIOLLEMSEN, A. T. M., VAALBURG, W. and FRANSSEN, E. J. F., 1998, Complete in vivo reversal of P-glycoprotein pump function in the blood—brain barrier visualised with positron emission tomography. British Journal of Pharmacology, 124, 1413–1418.
   Google Scholar
• HINDERLING, P. H. and HARTMANN, D., 1991, Pharmacokinetics of digoxin and main metabolites/ derivatives in healthy humans. Therapeutic Drug Monitoring, 13, 381–401.
   PubMed Web of Science ®Google Scholar
• HIROHASHI, T., SUZUKI, H., Pro, K., OGAWA, K., KIJME, K., SHIMIZU, T. and SUGIYAMA, Y., 1998, Hepatic expression of multidrug resistance-associated protein-like proteins maintained in Eisai hyperbilirubinemic rats. Molecular Pharmacology, 53, 1068–1075.
   PubMed Web of Science ®Google Scholar
• HIROHASHI, T., SUZUKI, H. and SUGIYAMA, Y., 1999, Characterisation of the transport properties of cloned multidrug resistance-associated protein 3 (MRP3), Journal of Biological Chemistry, 274, 15181–15185.
   Google Scholar
• HOFFMEYER, S., BURK, O., VON RICHTER, O., ARNOLD, H. P., BROCKMOLLER, J., JOHNE, A., CASCORBI, I., GERLO, T., ROOTS, I., EICHELBAUM, M. and BRINKMANN, U., 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. Proceedings of National Academy of Sciences, USA, 97, 3473–3478.
   PubMed Web of Science ®Google Scholar
• HOOIJBERG, J. H., BROXTERMAN, H. J., KOOL, M., ASSARAF, Y. G., PETERS, G. J., NOORDHUIS, P., SCHERER, R. J., BORST, P., PINED°, H. M. and JANSEN, G., 1999, Antifolate resistance mediated by the multidrug resistance proteins MRP1 and MRP2. Cancer Research, 59, 2532–2535.
   Google Scholar
• HOOIVELD, G. J. E. J., VAN MONTFOORT, J. E., MEIJER, D. K. F. and MULLER, M., 2000, Function and regulation of ATP-binding cassette transport proteins involved in hepatobiliary transport. European Journal of Pharmaceutical Sciences, 12, 13–30.
   Google Scholar
• HSIANG, B., ZHU, Y., WANG, Z., Wu, Y., SASSEVILLE, V., YANG, W.P. and KIRCHGESSNER, T. G., 1999, A novel human hepatic organic anion transporting polypeptide (OATP2). Journal of Biological Chemistry, 274, 37161–37168.
   PubMed Web of Science ®Google Scholar
• Hum-YuN, H., SECREST, D. T., MARK, K. S., CARNEY, D., BRANDQUIST, C., ELMQUIST, W. F. and MILLER, D. W., 1998, Expression of multidrug resistance-associated protein (MRP) in brain microvessel endothelial cells. Biochemical and Biophysical Research Communications, 243, 816–820.
   Google Scholar
• HUNTER, J. and HIRST, B. H., 1997, Intestinal secretion of drugs. The role of P-glycoprotein and related drug efflux systems in limiting oral drug absorption. Advanced Drug Delivery Reviews, 25, 129–157.
   Web of Science ®Google Scholar
• IBRAHIM, S., PEGGINS, J., KNAPTON, A., LICHT, T. and ASZALOS, A., 2000, Influence of antipsychotic, antiemetic and Ca2+ channel blocker drugs on the cellular accumulation of the anticancer drug daunorubicin: P-glycoprotein modulation. Journal of Pharmacology and Therapeutics, 295, 1276–1283.
   PubMed Web of Science ®Google Scholar
• INUI, K. I., MASUDA, S. and SAITO, H., 2000, Cellular and molecular aspects of drug transport in the kidney. Kidney International, 58, 944–958.
   PubMed Web of Science ®Google Scholar
• ITO, K., IWATSUBO, T., KANAMITSU, S., UEDA, K., SUZUKI, H. and SUGIYAMA, Y., 1998, Prediction of pharmacokinetic alterations caused by drug—drug interactions: metabolic interaction in the liver. Pharmacological Reviews, 50, 387–411.
   PubMed Web of Science ®Google Scholar
• ITO, S., KOREN, G. and HARPER, P. A., 1992, Energy-dependent transport of digoxin across renal tubular cell monolayers (LLC-PK1). Canadian Journal of Physiology and Pharmacology, 71, 40–47.
   Web of Science ®Google Scholar
• ISHIZUKA, H., KONNO, K., NAGANUMA, H., NISHIMURA, K., KOUZUKI, H., SUZUKI, H., STIEGER, B., MEIER, P. J. and SUGIYAMA, Y., 1998, Transport of temocaprilat into rat hepatocytes: role of organic anion transporting polypeptide. Journal of Pharmacology and Experimental Therapeutics, 287, 37–42.
   PubMed Web of Science ®Google Scholar
• ISHIZUKA, H., KONNO, K., NAGANUMA, H., SASAHARA, K., KAWAHARA, Y., NIIMURA, K., SUZUKI, H. and SUGIYAMA, Y., 1997, Temocaprilat, a novel angiotensin- converting enzyme inhibitor, is excreted in bile via an ATP-dependent active transporter (cMOAT) that is deficient in Eisai hyperbilirubinemic mutant rats (EHBR). Journal of Pharmacology and Experimental Therapeutics, 280, 1304–1311.
   PubMed Web of Science ®Google Scholar
• JANSEN, P. L. M., PETER, W. H. M. and LAMERS, W. H., 1985, Hereditary chronic conjugated hyperbilirubinaemia in mutant rats caused by defective hepatic anion transport Hepatology, 5, 573–579.
   Google Scholar
• JALAVA, K.M., PARTANEN, J. and NEUVONEN, P. J., 1997, Itraconazok decreases renal clearance of digoxin. Therapeutic Drug Monitoring, 19, 609–613.
   PubMed Web of Science ®Google Scholar
• JOHNE, A., BROCKMOLLER, J., BAUER, S., MAURER, A., LANGHEINRICH, M. and ROOTS, I., 1999, Pharmacokinetic interaction of digoxin with an herbal extract from St John's Wort (Hypericum perforatum). Clinical Pharmacology and Therapeutics, 66, 338–345.
   PubMed Web of Science ®Google Scholar
• JONKER, J. W., WEGENAAR, E., VAN DEEMETER, L., GOTTSCHILD, R., BENDER, H. M., DASENBROCK, J. and SCHINKEL, A. H., 1999, Role of the blood—brain barrier P-glycoprotein in limiting brain accumulation and sedative side-effects of asimadoline, a peripherally-acting analgesic drug. British Journal of Clinical Pharmacology, 127, 43–50.
   Web of Science ®Google Scholar
• KAJIHARA, S., HIZATOMI, A., MIZUTA, T., HARA, T., OZAKI, I., WADA, I. and YAMAMOTO, K., 1998, A splice mutation in the human canalicular multispecific organic anion transporter gene causes Dubin—Johnson syndrome. Biochemical et Biophysical Research Communications, 253, 454–457.
   PubMed Web of Science ®Google Scholar
• KAMIMOTO, Y., GATMAITAN, Z., Hsu, J. and ARIAS, I. M., 1989, The function of Gp170, the multidrug resistance gene product, in rat liver canalicular membrane vesicles. Journal of Biological Chemistry, 264, 11693–11698.
   PubMed Web of Science ®Google Scholar
• KARTENBECK, J., LEUSCHNER, U., MAYER, R. and KEPPLER, D., 1996, Absence of the canalicular isoform of the MRP gene-encoded conjugate export pump from the hepatocytes in Dubin—Johnson syndrome. Hepatology, 23, 1061-1 066.
   Google Scholar
• KATO, Y., IGARAsiti, T. and SUGIYMA, Y., 2000, Both cMoat/MRP2 and another unknown transporter(s) are responsible for the biliary excretion of glucuronide conjugate of the nonpeptide angiotensin II antagonist, telmisaltan. Drug Metabolism and Disposition, 28, 1146–1148.
   PubMed Web of Science ®Google Scholar
• KEPPLER, D. and ARIAS, I. M., 1997, Transport across the hepatocyte canalicular membrane. FASEB Journal, 11, 15–17.
   PubMed Web of Science ®Google Scholar
• KIM, R. B., 2000, Transporters in drug disposition. Current Opinion in Drug Discoveiy and Development, 3, 94–101.
   PubMedGoogle Scholar
• KIM, R. B., FROMM, M. F., WANDEL, C., LEAKE, B., WOOD, A. J. J., RODEN, D. M. and WILKINSON, G. R., 1998, The drug transporter P-glycoprotein limits oral absorption and brain entry of HIV-1 protease inhibitors. Journal of Clinical Investigation, 101, 289–294.
   Google Scholar
• KIM, R. B., LEAKE, B., CHOO, E., DRESSER, G. K., KUBBA, S. V., SCHWARZ, U. I., TAYLOR, A., XIE, HG., STEIN, C. M., WOOD, A. J. J., MCKINSEY, J., SCHUETZ, E. G., SCHUETZ, J. D. and WILKINSON, G. R., 2000, Identification of functionally important MDR1 variant alleles among African-American and Caucasian subjects. Drug Metabolism Reviews, 32 (suppl. 2), 199.
   PubMed Web of Science ®Google Scholar
• KIM, R. B., WANDEL, C., LEAKE, B., CVETKOVIC, M., FROMM, M. F., DEMPSEY, P. J., RODEN, M. M., BELAS, F., CHAUDHARY, A. K., RODEN, D. M., WOOD, A. J. J. and WILKINSON, G. R., 1999, Interrelationship between substrates and inhibitors of human CYP3A and P-glycoprotein. Pharmaceutical Research, 16, 408–414.
   Google Scholar
• KLEIN, I., SAKARDI, B. and VARADI, A., 1999, An inventory of the human ABC proteins. Biochimica et Biophyska Acta, 1461, 237–262.
   PubMed Web of Science ®Google Scholar
• KOEPSELL, H., 1998, Organic cation transporters in intestine, kidney, liver and brain. Annual Review of Physiology, 60, 243–266.
   PubMed Web of Science ®Google Scholar
• ICONIG, J., Cui, Y., NIES, A. T. and KEPPLER, D., 2000a, A novel human organic anion transporting polypeptide localised to the basolateral hepatocyte membrane. American Journal of Physiology and Gastrointestinal Liver Physiology, 278, G156—G164.
   Web of Science ®Google Scholar
• KONIG, J., Cui, Y., NIES, A. T. and KEPPLER, D., 2000b, Localisation and genomic organisation of a new hepatocellular organic anion transporting polypeptide. Journal of Biological Chemistry, 275, 23161–23168.
   PubMed Web of Science ®Google Scholar
• KONno, J., Nips, A. T., Cm, Y., LEIER, I. and KEPPLER, D., 1999a, Conjugate export pumps of the multidrug resistance protein (MRP) family: localisation, substrate specificity, and MRP2-mediated drug resistance. Biochimica et Biophysica Ada, 1461, 377–394.
   PubMed Web of Science ®Google Scholar
• KONIU, J., ROST, D., Cm, Y. and KEPPLER, D., 1999b, Characterization of the human multidrug resistance protein isoforrn MRP3 localized to the basolateral hepatocyte membrane, Hepatology, 29, 1156–1163.
   Google Scholar
• KOOL, M., DE HAAS, M., SCHEER, G. L., SCHEPER, R. J., VAN EIJIK, M. J. T., JuuN, J. A., BAAS, F. and BORST, P., 1997, Analysis of expression of cMOAT (MRP2), MRP3, MRP4 and MRP5, homologues of the multidrug resistance-associated protein gene (MRP1), in human cancer cell lines. Cancer Research, 57, 3537–3547.
   Google Scholar
• KOOL, M., VAN DER LINDEN, M., DE HAAS, M., SCHEER, G. L., DE VIE, J. M. L., SMITH, A. J., JANSEN, G., PETERS, G. J., PONNE, N., SCHEPER, R. J., OUDE-ELFERINK, R. P. J., Bs, F. and BORST, P., 1999, MRP3 an organic anion transporter able to transport anticancer drugs. Proceedings of the National Academy of Sciences, USA, 96, 6914–6919.
   Google Scholar
• KOVARIK, J. M., RIGAUDY, L., GUERRET, M., GERBEAU, C. and ROST, K.L., 1999, Longitudinal assessment of P-glycoprotein-mediated drug interaction of valspodar on digoxin. Clinical Pharmacology and Therapeutics, 66, 391–400.
   PubMed Web of Science ®Google Scholar
• KUIPERS, F., ENSERINK, E., VAN DER STEEN, A. B. M., HARDONK, M. J., FEVERY, J. and VONK, R. J., 1988, Separate transport systems for biliary excretion of sulfated and unsulfated bile acid in the rat. Journal of Clinical Investigation, 81, 1593–1599.
   Google Scholar
• KULLAK-UBLICK, G.A., 1999, Regulation of organic anion and drug transporters of the sinusoidal membrane. Journal of Hepatology, 31, 563–573.
   PubMed Web of Science ®Google Scholar
• KUSUHARA, H., SEKINE, T., UTSUNOMIYA-TATE, N., TSUDA, M., KOJIMA, R., Ho CHA, S., SUGIYAMA, Y., KANAI, Y. and ENDOU, H., 1999, Molecular cloning and characterisation of a new multispecific organic anion transporter from rat brain. Journal of Biological Chemistry, 274, 13675–13680.
   Google Scholar
• KUSUHARA, H., SUZUKI, H., NAITO, M., TSURUO, T. and SUGIYAMA, Y., 1998, Characterisation of efflux transport of organic anions in a mouse brain capillary endothelial cell line. Journal of Pharmacology and Experimental Therapeutics, 285, 1260–1265.
   PubMed Web of Science ®Google Scholar
• KUSUHARA, H., SUZUKI, H., TERASAKI, T., KAKEE, A., LEMAIRE, M. and SUGIYAMA, Y., 1997, P-glycoprotein mediates the efflux of quinidine across the blood-brain barrier. Journal of Pharmacology and Experimental Therapeutics, 283, 574–580.
   PubMed Web of Science ®Google Scholar
• LAVE, T., PORTMANN, R., SCHENKER, G., GIANNI, A., GUENZI, A., GIROMETTA, M.A. and SCHMITT, M., 1999, Interspecies pharmacokinetic comparisons and allometric scaling of napsagatran, a low molecular weight thrombin inhibitor. Journal of Pharmacy and Pharmacology, 51, 85–91.
   PubMed Web of Science ®Google Scholar
• LAVE, T., SANER, A., COASSOLO, P., BRANDT, R., SCHMITT-HOMANN, A. H. and CHOU, R. C., 1996, Animal pharmacokinetics and interspecies scaling from animals to man of lamifiban, a new platelet aggregation inhibitor. Journal of Pharmacy and Pharmacology, 48, 573–577.
   Google Scholar
• LEBLANC, G. A., 1994, Hepatic vectorial transport of xenobiotics. Chemico-Biological Interactions, 90, 101–120.
   PubMed Web of Science ®Google Scholar
• LEMAIRE, M., BRUELISAKER, A., GUNTZ, P. and SATO, H., 1996, Dose-dependent brain penetration of SDZ PSC833, a novel multidrug resistance reversing cyclosporin, in rat. Cancer Chemotherapy and Pharmacology, 38, 481–486.
   PubMed Web of Science ®Google Scholar
• LETRENT, S. P., POLLACK, G. M., BROUWER, K. R. and BROUWER, K. L. R., 1998, Effect of GF12091 8, a potent P-glycoprotein inhibitor, on morphine pharmacokinetics and pharmacodynamics in the rat. Pharmaceutical Research, 15, 599–605.
   PubMed Web of Science ®Google Scholar
• LETRENT, S. P., POLLACK, G. M., BROUWER, K. R. and BROUWER, K. L. R., 1999, Effects of a potent and specific P-glycoprotein inhibitor on the blood-brain barrier distribution and antinociceptive effect of morphine in the rat. Drug Metabolism and Disposition, 27, 827–834.
   PubMed Web of Science ®Google Scholar
• LEVIN, V. A., 1980, Relationship of octanollwater partition coefficient and molecular weight to rat brain capillary permeability. Journal of Medicinal Chemistry, 23, 682–684.
   PubMed Web of Science ®Google Scholar
• LI, L., LEE, T. K., MEIER, P. J. and BALLATORI, N., 1998, Identification of glutathione as a driving force and leukotriene C4 as a substrate for oatpl, the hepatic sinusoidal organic solute transporter. Journal of Biological Chemistry, 273, 16184–16191.
   PubMed Web of Science ®Google Scholar
• LI, L., MEIER, P. J. and BALLATORI, N., 2000, Oatp2 mediates bidirectional organic solute transport: a role for intracellular glutathione. Molecular Pharmacology, 58, 335–340.
   PubMed Web of Science ®Google Scholar
• LIN, J. H., 1995, Species similarities and differences in pharmacokinetics. Drug Metabolism and Disposition, 23, 1008–1021.
   PubMed Web of Science ®Google Scholar
• LIN, J. H., CHIBA., M. and BAILLIE, T. A., 1999, Is the role of the small intestine in first-pass metabolism overestimated? Pharmacological Reviews, 51, 135–157.
   Google Scholar
• LIPPERT, C., LING, J., BROWN, P., BURNASTER, S., ELLER, M., CHENG, L., THOMPSON, R. and WIER, S., 1995, Mass balance and pharmacokinetics of MDL 16455A in healthy male volunteers. Pharmaceutical Research, 12 (suppl. 9), S390.
   Google Scholar
• LOWN, K. S., FONTANA, R. J., SCHMIEDLIN-REN, P., TURGEON, D. K. and WATKINS, P. B., 1995, Interindividual variation in intestinal mdrl expression: lack of short term dietary effects. Gastroenterology, 108, A737.
   Google Scholar
• LOWN, K. S., MAYO, R. R., LEICHTMAN, A. B., HSIAO, H. L., TURGEON, D. K., SCHMIEDLIN-REN, P., BROWN, M. B., Guo, W., Rossi, S. J., BENET, L. Z. and WATKINS, P. B., 1997, Role of intestinal P-glycoprotein (mdrl) in interpatient variation in the oral bioavailability of cyclosporine. Clinical Pharmacology and Therapeutics, 62, 248–260.
   Google Scholar
• MASSARELLA, J. W., NAZARENO, L. A., PASSE, S. and MIN, B., 1996, The effect of probenecid on the pharmacokinetics of zalcitabine in HIV-positive patients. Pharmaceutical Research, 13, 449–452.
   PubMed Web of Science ®Google Scholar
• MAYER, U., WAGENAAR, E., BEIJNEN, J. H., SMIT, J. W., MEIJER, D. K. F., VAN ASPEREN, J., BORST, P. and SCHINKEL, A. H., 1996, Substantial excretion of digoxin via the intestinal mucosa and prevention of long-term digoxin accumulation in the brain by the mdrl a P-glycoprotein. British Journal of Pharmacology, 119, 1038–1044.
   Google Scholar
• MAYER, U., WAGENAAR, E., DOROBEK, B., BEIJNEN, J. H., BORST, P. and SCHINKEL, A. H., 1997, Full blockade of intestinal P-glycoprotein and extensive inhibition of blood—brain barrier P-glycoprotein by oral treatment of mice with P5C833. journal of Clinical Investigation, 100, 2430–2436.
   PubMed Web of Science ®Google Scholar
• MEIER, P. J., ECKHARDT, U., SCHROEDER, A., HAGENBUCH, B. and STIEGER, B., 1997, Substrate specificity of sinusoidal bile acid and organic anion uptake systems in rat and human liver. Hepatology, 26, 1667-1 677.
   Google Scholar
• MEIJER, D. K. F., Mot, W. E. M., MULLER, M. and KURZ, G., 1990, Carrier-mediated transport in the hepatic distribution and elimination of drugs with special reference to the category of organic cations. Journal of Pharmacokinetics and Biopharmaceutks, 18, 35–70.
   Google Scholar
• MEIJER, D. K. F., SMIT, J. W. and MULLER, M., 1997, Hepatobiliary elimination of cationic drugs: the role of P-glycoproteins and other ATP-dependent transporters Advanced Drug Delivery Reviews, 25, 159–200.
   Google Scholar
• MILNE, R. J. and BUCKLEY, M. T., 1991, Celiprolol: an updated review of its pharmacokinetic properties and therapeutic efficacy in cardiovascular diseases. Drugs, 41, 941–969.
   PubMed Web of Science ®Google Scholar
• MILNE, R. W., LARSEN, L. A., JORGENSEN, K. L., BASTLUND, J. F., STRETCH, G. L. and EVANS, A. M., 2000, Fexofenadine: a substrate for OATP and P-GP in the liver. Paper presented at the Millennium World Congress of Pharmaceutical Sciences, San Francisco, CA, 1 6–20 April.
   Google Scholar
• MIMAKI, T., NOZAKI, T., TAGAYA, O., HOSOKAWA, S., NAKURA, T., Mom, H., KONDOU, S., MATSUBARA, Y. and OuGon, T., 1986, The character of a new mutant in rats with hyperbilrubinuria syndrome. Cong. Anom., 26, 250–251.
   Google Scholar
• MORGAN, P., BEAUMONT, K., FENNER, K., LEAKE, B. and Kim, R. B., 1999, Identification of OATP-me diated uptake of a series of lipophilic bases. Paper presented at the 9th North American I SSX Meeting, Nashville, TN, 25–29 October.
   Google Scholar
• MULLER, M. and JANSEN, P. L. M., 1997, Molecular aspects of hepatobiliary transport American Journal of Physiology, 272, G1285—G1303.
   Google Scholar
• MULLER, M. and JANSEN, P. L. M., 1998, The secretory function of the liver: new aspects of hepatobiliary transport. Journal of Hepatology, 28, 344–354.
   PubMed Web of Science ®Google Scholar
• NADEMANEE, K., KANNAN, R., HENDRICKSON, J., OOKHTENS, M., KAY, I. and SINGH, B. N., 1984, Amiodarone-digoxin interaction: clinical significance, time-course of development, potential pharmacokinetic mechanisms and therapeutic implications. Journal of American College of Cardiology, 4, 111–116.
   PubMed Web of Science ®Google Scholar
• NAGEL, G., VOLK, C., FRIEDRICH, T., ULZHEIMER, J. C., BAMBERG, E. and KOEPSELL, H., 1997, A reevaluation of substrate specificity of the rat cation transporter rOCT1. Journal of Biological Chemistry, 272, 31953–31956.
   PubMed Web of Science ®Google Scholar
• NOBLE, S. and FAULDS, D., 1996, Saquinavir: a review of its pharmacology and clinical potential in the management of HIV infection. Drugs, 52, 93–112.
   PubMed Web of Science ®Google Scholar
• OUDE ELFERINK, R. P. J., MEIJER, D. K. F., KUIPERS, F., JANSEN, P. L. M., GROEN, A. K. and GROOTHUIS, G. M. M., 1995, Hepatobiliary secretion of organic compounds; molecular mechanisms of membrane transport. Biochimica et Biophysica Acta, 1241, 215–268.
   Google Scholar
• PAHLMAN, I., EDHOL M., KANKAANRANTHA S. and ODELL, M.L., 1998, Pharmacokinetics of susalimod, a highly biliary-excreted sulphasalazine analogue, in various species. Nonpredictable human clearance by allometric scaling. Pharmacy and Pharmacology Communications, 4, 493–498.
   Google Scholar
• PARTANEN, J., JALAVA, K. M. and NEUVONEN, P. J., 1996, Itraconazole increases serum digoxin concentrations. Pharmacology and Toxicology, 79, 274–276.
   PubMedGoogle Scholar
• PAULUSMA, C. C., KOOL, M., BOSMA, P. J., SCHEER, G. L., TER BORG, F., SCHEPER, R. J., TYTGAT, G. N., BORST, P., Bs, F. and OUDE ELFERINK, R. P. J., 1997, A mutation in the human canalicular multispecific organic anion transporter gene causes the Dubin—Johnson syndrome Hepatology, 25, 1539–1 542.
   Google Scholar
• PEDERSEN, K. E., CHRISTIANSEN, B. D., KLITGAARD, N. A. and NIELSEN-KUDSK, F., 1983, Effect of quinidine on digoxin bioavailability. European Journal of Clinical Pharmacology, 24, 41–47.
   Google Scholar
• PETZINGER, E., 1994, Transport of organic anions in the liver. An update on bile acid, fatty acid, monocarboxylate, anionic amino acid, cholephilic organic anion and anionic drug transport. Review of Physiology and Biochemical Pharmacology, 123, 47–211.
   PubMed Web of Science ®Google Scholar
• POLLI, J. W., JARRETT, J. L., STLIDENBERG, S. D., HUMPHREYS, J. E., DENNIS, S. W., BROUWER, K. R. and WOOLLEY, J. L., 1999, Role of P-glycoprotein on the CNS disposition of amprenavir (141W94), an HIV protease inhibitor. Pharmaceutical Research, 16, 1206–1212.
   PubMed Web of Science ®Google Scholar
• PRITCHARD, J. B. and MILLER, D. S., 1997, Renal secretion of organic cations: a multistep process. Advanced Drug Delivery Reviews, 25, 231–242.
   Web of Science ®Google Scholar
• RAHKIT, A., HOLFORD, N. H., GUENTERT, T. W., MALONEY, K. and RIEGELMAN, S., 1984, Pharmacokinetics of quinidine and three of its metabolites in man. Journal of Pharmacokinetks and Biopharmaceutics, 12, 1–21.
   PubMedGoogle Scholar
• REICHEL, C., GAO, B., VAN MONTFOORT, J., CATTORI, V., RAHNER, C., HAGENBUCH, B., STIEGER, B., KAMISAKO, T. and MEIER, P. J., 1999, Localisation and function of the organic anion transporting polypeptide Oatp2 in rat liver. Gastroenterology, 117, 688–695.
   PubMed Web of Science ®Google Scholar
• ROBBINS, D. K., CASTLES, M. A., PACK, D. J., BHARGAVA, V. O. and WEIR, S. J., 1998, Dose proportionality and comparison of single and multiple dose pharmacokinetics of fexofenadine (MDL 16455) and its enantiomers in healthy male volunteers. Biopharmaceutks and Drug Disposition, 19, 455–463.
   PubMed Web of Science ®Google Scholar
• ROY CHOWDHURY, J., ROY CHOWDHURY, N., WOLFKO, A. W. and ARIAS, I. M., 1994, Heme and bile pigment metabolism. In I. M. Arias, J. L. Boyer, N. Fausto, W. B. Jakoby, D. A. Schachter and D. A. Shafritz (eds), The Liver: Biology and Pathobiology (New York: Raven), pp. 471–504.
   Google Scholar
• SADEQUE, A. J. M., WANDEL, C., HE, H., SHAH, S. and WOOD, A. J. J., 2000, Increased drug delivery to the brain by P-glycoprotein inhibition. Clinical Pharmacology and Therapeutics, 68, 231–237.
   Google Scholar
• SAEKI, T., UEDA, K., TANIGAWARA, Y., HORI, R. and KOMANO, T., 1993, Human P-glycoprotein transports cyclosporin A and FK506. Journal of Biological Chemistry, 268, 6077–6080.
   PubMed Web of Science ®Google Scholar
• SANDKER, G. W., WEERT, B., OLINGA, P., WOLTERS, H., SLOOF, M. J. H., MEIJER, D. K. F. and GROOTHIUS, G. M. M., 1994, Characterisation of transport in isolated human hepatocytes. Biochemical Pharmacology, 47, 2193–2200.
   Google Scholar
• SATHIRAKUL, K., SUSUKI, H., YAMADA, T., HANANO, M. and SUGIYAMA, Y., 1994, Multiple transport systems for organic anions across the bile canalicular membrane. Journal of Pharmacology and Experimental Therapeutics, 268, 65–73.
   PubMed Web of Science ®Google Scholar
• SASABE, H., TERASAKI, T., Tsuji, A. and SUGIYAMA, Y., 1997, Carrier-mediated hepatic uptake of quinolone antibiotics in the rat. Journal of Pharmacology and Experimental Therapeutics, 282, 162–171.
   PubMed Web of Science ®Google Scholar
• SASABE, H., Tsuji, A. and SUGIYAMA, Y., 1998, Carrier-mediated mechanism for the biliary excretion of the quinolone antibiotic grepafloxacin and its glucuronide in rats. Journal of Pharmacology and Experimental Therapeutics, 284, 1033–1039.
   PubMed Web of Science ®Google Scholar
• SCHINKEL, A. H., 1999, P-glycoprotein, a gatekeeper in the blood—brain barrier. Advanced Drug Delivery Reviews, 36, 179–194.
   PubMed Web of Science ®Google Scholar
• SCHINKEL, A. H., SMIT, J. J., VAN TELLINGEN, O., BEIJEN, J. H., WAGENAAR, E., VAN DEEMTER, L., MOL, C. A. A. M., VAN DER VALK, M. A., ROBANUSMAANDAG, E. C. and BORST, P., 1994, Disruption of the mouse mdrla P-glycoprotein gene leads to a deficiency in the blood—brain barrier and to increased sensitivity to drugs, Cell, 77, 491–502.
   Google Scholar
• SCHINKEL, A. H., WAGENAAR, E., MOLS, C. A. A. M., VAN DEEMTER, L., 1996, P-glycoprotein in the blood—brain barrier of mice influences the brain penetration and pharmacological activity of many drugs. Journal of Clinical Investigation, 97, 2517–2524.
   Google Scholar
• SCHINKEL, A. H., WAGENAAR, E., VAN DEEMTER, L., Mot, C. A. A. M. and BORST, P., 1995, Absence of the mdrla P-glycoprotein in mice affects tissue distribution and pharmacokinetics of dexamethasone, digoxin and cyclosporin A. Journal of Clinical Investigation, 96, 1698–1705.
   Google Scholar
• SCHRENK, D., GANT, T. W., PREISEGGER, K.H., SILVERNMAN, J. A., MARINO, P. and THORGEIRSSON, S. S., 1993, Induction of multidrug resistance gene expression during cholestasis in rats and nonhuman primates. Hepatology, 17, 854–860.
   PubMed Web of Science ®Google Scholar
• SCHWARZ, U. I., GRAMATTE, T., KRAPPWEIS, J., BERNDT, A., OERTEL, R., VON RICHTER, O. and KIRCH, W., 1999, Unexpected effect of verapamil on oral bioavailability of the [3-blo cker talinolol in humans. Clinical Pharmacology and Therapeutics, 65, 283–290.
   PubMed Web of Science ®Google Scholar
• SEKINE, T., CHA, S. H., KANAI, Y. and ENDOU, H., 1999, Molecular biology of multispecific organic anion transporter family (OAT family). Clinical and Experimental Nephrology, 3, 237–243.
   Google Scholar
• SEKINE, T., WATANABE, N., HOSOYAMADA, M., KANAI, Y. and ENDOU, H., 1997, Expression cloning and characterisation of a novel multispecific organic anion transporter. Journal of Biological Chemistry, 272, 18526–18529.
   PubMed Web of Science ®Google Scholar
• SM., M. V., AUDUS, K. L. and BORCHARDT, R. T., 1989, The application of bovine brain microvessel endothelial-cell monolayers grown onto polycarbonate membranes in vitro to estimate the potential permeability of solutes through the blood—brain barrier, Pharmaceutical Research, 6, 624–627.
   Google Scholar
• SHI, X., BAI, S., FORD, A. C., BURR, R. D., JACQUEMIN, E., HAGENBUCH, B., MEIER, P. J. and WOLKO, A. W., 1995, Stable inducible expression of a functional rat liver organic anion transport protein in HeLa cells. Journal of Biological Chemistry, 270, 25591–25595.
   PubMed Web of Science ®Google Scholar
• SHIBATA, N., HOSHINO, N., MINOUCHI, T., YAMAI, A., PARK, K., TOMOYOSHI, T., ABE, H. and KODAMA, M., 1998, Relationship between area under the concentration versus time curve of cyclosporin A, creatinine clearance, hematocrit value, and other clinical factors in Japanese renal transplant patients. International Journal of Clinical Pharmacology and Therapeutics, 36, 202–209.
   PubMed Web of Science ®Google Scholar
• SIKIC, B. I., FISHER, G. A. and Lum, B. L., 1997, Modulation and prevention of multidrug resistance by inhibitors of P-glycoprotein. Cancer Chemotherapy and Pharmacology, 40 (suppl.), S13–S19.
   Google Scholar
• SMIT, J. J. M., SCHINKEL, A. H., OUDE ELFERINK, R. P. J., GROEN, A. K., WAGENAAR, E., VAN DEEMTER, L., MOL, C. A. A. M., OTTENHO, R., VAN DER LUGT, N. M., VAN ROON, M. A., VAN DER VALK, M. A., OERHAUS, G. J. A., BERNS, A. J. M. and BORST, P., 1993, Homozygous disruption of the murine mdr2 P-glycoprotein gene leads to a complete absence of phospholipid from bile and to liver disease. Cell, 75, 451–462.
   Google Scholar
• SMIT, J. W., SCHINKEL, A. H., BORST, P. and MEIJER, D. K. F., 1996, Involvement of P-glycoprotein in the biliary and intestinal excretion of amphiphilic drugs: mdr gene knock out studies. Hepatology, 24, 351.
   Web of Science ®Google Scholar
• SMIT, J. W., SCHINKEL, A. H, WEERT, B. and MEIJER, D. K. F., 1998, Hepatobiliary and intestinal clearance of amphiphilic cationic drugs in mice in which both mdrl a and mdrlb genes have been disrupted. British Journal of Pharmacology, 124, 416–424.
   PubMed Web of Science ®Google Scholar
• SMITH, A. J., DEVREEE, J. M. L., OTTENHO, R., OUDE ELFERINK, R. P. J., SCHINKEL, A. H. and BORST, P., 1998, Hepatocyte-specific expression of the human MDR3 P-glycoprotein restores the biliary phosphatidylcholine excretion absent in Mdr2(-/-) mice. Hepatology, 28, 530–536.
   Google Scholar
• SMITH, A. J., VAN HELVOORT, A., VAN MEER, G., SZABO, K., WELKER, E., SZAKACS, G., VARADI, A., SARKADI, B. and BORST, P., 2000, MDR2 P-glycoprotein, a phosphatidylcholine translocase, transports several cytotoxic drugs and directly interacts with drugs as judged by interference with nucleotide trapping. Journal of Biological Chemistry, 275, 23530–23539.
   PubMed Web of Science ®Google Scholar
• SMITH, D. A. and JONES, B. C., 1992, Speculations on the substrate structure-activity relationships of cytochrome P450 enzymes. Biochemical Pharmacology, 44, 2089–2098.
   PubMed Web of Science ®Google Scholar
• SMITH, D. A., JONES, B. C. and WALKER, D. K., 1996, Design of drugs involving concepts and theories of drug metabolism and pharmacokinetics. Medicinal Research Reviews, 16, 243–266.
   PubMed Web of Science ®Google Scholar
• SOMOGYI, A., 1996, Renal transport of drugs: specificity and molecular mechanisms. Clinical and Experimental Pharmacology and Physiology, 23, 986–989.
   PubMed Web of Science ®Google Scholar
• SPAHN-LANGGUTH, H., BAKTIR, G., RADSCHUWEIT, A., OKYAR, A., TERHAAG, B., ADER, P., HANAFY, A. and LANGuum, P., 1998, P-glycoprotein transporters and the gastrointestinal tract: evaluation of the potential in vivo relevance of in vitro data employing talinolol as model compound. International Journal of Clinical Pharmacology and Therapeutics, 36, 16–24.
   PubMed Web of Science ®Google Scholar
• SPEEG, K. V. and MALDONADO, A. L., 1994, Effect of the nonimrnunosupressive cyclosporin analog SDZ PSC-833 on colchicine and doxorubicin biliary secretion by the rat in vivo. Cancer Chemotherapy and Pharmacology, 34, 133–136.
   PubMed Web of Science ®Google Scholar
• SPRINZ, H. and NELSON, R. S., 1954, Persistent nonhemolytic hyperbilirubinemia associated with lipochrome-like pigment in liver cells; report of four cases. Annals of International Medicine, 41, 952–962.
   PubMed Web of Science ®Google Scholar
• SPARREBOOM, A., VAN ASPEREN, J., MAYER, U., SCHINKEL, A. H., SMIT, J. W., MEIJER, D. K. F., BORST, P., NOOIJEN, W. J., BEIJNEN, J. H. and VAN TELLINGEN, O., 1997, Limited oral bioavailability and active epithelial excretion of paclitaxel (taxol) caused by P-glycoprotein in the intestine. Proceedings of the National Academy Sciences, USA, 94, 2031–2035.
   Google Scholar
• STIEGER, B. and MEIER, P., 1998, Bile acid and xenobiotic transporters in liver. Current Opinions in Cell Biology, 10, 462–467.
   PubMed Web of Science ®Google Scholar
• SUZUM, H. and SUGIYAMA, Y., 2000, Role of metabolic enzymes and efflux transporters in the absorption of drugs from the small intestine. European Journal of Pharmaceutical Sciences, 12, 3–12.
   PubMed Web of Science ®Google Scholar
• TAMAI, I., NEZU, J., UCHINO, H., SAI, Y., OKU, A., SHIMANE, M. and TSUJI, A., 2000, Molecular identification and characterisation of novel members of the human organic anion transporter (OATP) family. Biochemical and Biophysical Research Communications, 273, 251–260.
   PubMed Web of Science ®Google Scholar
• TAMAI, I. and Tsuji, A., 2000, Transporter-mediated permeation of drugs across the blood-brain barrier. Journal of Pharmaceutical Sciences, 89, 1371–1388.
   PubMed Web of Science ®Google Scholar
• TAKENAKA, O., HORIE, T., KOBAYASHI, K., SUZUKI, H. and SUGIYAMA, Y., 1995a, Kinetic analysis of hepatobiliary transport for conjugated metabolites in the perfused liver of mutant rats (EHBR) with hereditary conjugated hyperbilirubinemia. Pharmaceutical Research, 12, 1 746–1755.
   PubMed Web of Science ®Google Scholar
• TAKENAKA, O., HORIE, T., SUZUKI, H. and SUGIYAMA, Y., 1995b, Different biliary excretion systems for glucuronide and sulfate of a model compound; study using Eisai hyperbilirubinemic rats. Journal of Pharmacology and Experimental Therapeutics, 274, 13262–1369.
   Web of Science ®Google Scholar
• THIEBAUT, F., TSURURO, T., HAMADA, H., GOTTESMAN, M. M., PASTAN, I. and WILLINGHAM, M. C., 1987, Cellular localisation of the multidrug resistance gene product in normal human tissues. Proceedings of National Academy of Sciences, USA, 84, 7735–7738.
   PubMed Web of Science ®Google Scholar
• THOMPSON, S. J., KOSZDIN, K. and BERNARDS, C. M., 2000, Opiate-induced analgesia is increased and prolonged in mice-lacking P-glycoprotein. Anaesthesiology, 92, 1392–1399.
   PubMed Web of Science ®Google Scholar
• THWAITES, D. T., CAVET, M., HIRST, B. H. and SIMMONS, N. L., 1995, Angiotensin- converting enzyme (ACE) inhibitor transport in human intestinal epithelial (Caco-2) cells. British Journal of Pharmacology, 114, 981–986.
   PubMed Web of Science ®Google Scholar
• TOH, S., WADA, M., UCHIUMI, T., INOKUCHI, A., MAKIN, Y., HORIE, Y., ADACHI, Y., SAKIZAKA, S. and KUWANAO, M., 1999, Genomic structure of the canalicular multispecific organic anion-transporter gene (MRP2/cMOAT) and mutations in the ATP-binding-cassette region in Dubin—Johnson syndrome. American Journal of Human Genetics, 64, 739–746.
   PubMed Web of Science ®Google Scholar
• TRAUSCH, B., °ERTEL, R., RICHTER, K. and GRAMATTE, T., 1995, Disposition and bioavailability of the /31-adrenoceptor antagonist talinolol in man. Biopharmaceutics and Drug Disposition, 16, 403–414.
   Google Scholar
• TSUJI, A. and TAMAI, T., 1996, Carrier-mediated intestinal transport of drugs. Pharmaceutical Research, 13, 963–977.
   PubMed Web of Science ®Google Scholar
• TSUJI, H., KONIG, J., ROST, D., STOCKEL, B., LEUSCHNER, U. and KEPPLER, D., 1999, Exon—intron organization of the human multidrug-resistance protein 2 (MRP2) gene mutated in Dubin—Johnson syndrome. Gastroenterology, 117, 653–660.
   PubMed Web of Science ®Google Scholar
• URAKAMI, Y., OKUDA, M., MASUDA, S., SAITO, H. and INui, K. I., 1998, Functional characteristics and membrane localisation of rat multispecific organic cation transporters, OCT1 and OCT2, mediating tubular secretion of cationic drugs. Journal of Pharmacology and Experimental Therapeutics, 287, 800–805.
   PubMed Web of Science ®Google Scholar
• VAN ASPEREN, J., MAYER, U., VAN TELLINGEN, O. and BEIJNEN, J. H., 1997, The functional role of P-glycoprotein in the blood—brain barrier. Journal of Pharmaceutical Sciences, 86, 881–884.
   PubMed Web of Science ®Google Scholar
• VAN ASPEREN, J., SCHINKEL, A. H., BEIJNEN, J. H., NOOIJEN, W. J., BORST, P. and VAN TELLINGEN, O., 1996, Altered pharmacokinetics of vinblastine in mdrla P-glycoprotein-deficient mice. Journal of National Cancer Institute, 88, 994–999.
   PubMedGoogle Scholar
• VAN ASPEREN, J., VAN TELLINGEN, O. and BEIJNEN, J. H., 2000, The role of MDR1A P-glycoprotein in the biliary and intestinal secretion of doxorubicin and vinblastine in mice. Drug Metabolism and Disposition, 28, 264–267.
   PubMed Web of Science ®Google Scholar
• VAN MONTFOORT, J. E., HAGENBUCH, B., FATTINGER, K. E., MULLER, M., GROOTHUIS, G. M. M., MEIJER, D. K. F. and MEIER, P. J., 1999, Polyspecific organic anion transporting polypeptides mediate hepatic uptake of amphipathic type II organic cations. Journal of Pharmacology and Experimental Therapeutics, 291, 147–152.
   Google Scholar
• VAN VLIET, A. K., VAN THIEL, C. F., HUSIMAN, R. H., MOSHAGE, H., YAP, S. H. and COHEN, L. H., 1995, Different effects of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors on sterol synthesis in various human cell types. Biochimka et Biophysica Acta, 1254, 105–111.
   PubMed Web of Science ®Google Scholar
• VERSCHRAAGEN, M., KOKS, C. H. W., SCHELLENS, J. H. M. and BEIJNEN, J. H., 1999, P-glycoprotein system as a determinant of drug interactions: the case of digoxin-verapamil. Pharmacological Research, 40, 301–306.
   Google Scholar
• VON MOLTKE, L. L., GREENBLATT, D. J., SCHMIDER, J., WRIGHT, C. E., HARMATZ, J. S. and SHADER, R. I., 1998, In vitro approaches to predicting drug interactions in vivo. Biochemical Pharmacology, 55, 113–122.
   PubMed Web of Science ®Google Scholar
• WACHER, V. J., SALPHATI, L. and BENET, L. Z., 1996, Active secretion and enterocytic drug metabolism barriers to drug absorption. Advanced Drug Delivery Reviews, 20, 99–112.
   Web of Science ®Google Scholar
• WACHER, V. J., Wu, C.Y. and BENET, L. Z., 1995, Overlapping substrate specificities and tissue distribution of cytochrome P450 3A and P-glycoprotein: implications for drug delivery and activity in cancer chemotherapy. Molecular Carcinogenesis, 13, 129–134.
   PubMed Web of Science ®Google Scholar
• WADA, M., TOH, S., TANIGUCHI, K., NAKAMURA, T., UCHIUMI, T., KOHNO, K., YOSHIDA, I., KIMURA, A., SAKZAKA, S., ADACHI, Y. and KIJWANO, M., 1998, Mutations in the canalicular multispecific organic anion transporter (cMOAT) gene, a novel ABC transporter, in patients with hyperbilirubinemia II Dubin—Johnson syndrome. Human Molecular Genetics, 7, 203–207.
   PubMed Web of Science ®Google Scholar
• WANDEL, C., KIM, R. B., KAPP, S., GUENGERICH, F. P., WILKINSON, G. R. and WOOD, A. J. J., 1999, P-glycoprotein and cytochrome P-450 3A inhibition: dissociation of inhibitory potencies. Cancer Research, 59, 3944–3948.
   PubMed Web of Science ®Google Scholar
• WASHINGTON, C. B., WILTSHIRE, H. R., MAN, M., MOY, T., HARRIS, S. R., WORTH, E., WEIGL, P., LIAND, Z., HALL, D., MARRIOT, L. and BLASCHKE, T. F., 2000, The disposition of Saquinavir in normal and P-glycoprotein deficient mice, rats, and in cultured cells, Drug Metabolism and Disposition, 28, 1058–1062.
   Google Scholar
• WATKINS, P. B., 1997, The barrier function of CYP3A4 and P-glycoprotein in the small bowel. Advanced Drug Delivery Reviews, 27, 161–170.
   PubMed Web of Science ®Google Scholar
• WATKINS, P. B., 1999, Approaches to Studying the Role of Transporters in Drug Interactions in Man. International Congress Series 1178 (Variability in Human Drug Response), pp. 55–67.
   Google Scholar
• WESTPHAL, K., WEINBRENNER, A., GIESSMANN, T., STUHR, M., FRANKE, G., ZSCHIESCHE, M., °ERTEL, R., TERHAAG, B., KROEMER, H. K. and SIEGMUND, W., 2000a, Oral bioavailability of digoxin is enhanced by talinolol: Evidence for involvement of intestinal P-glycoprotein. Clinical Pharmacology and Therapeutics, 68, 6–12.
   Google Scholar
• WESTPHAL, K., WEINBRENNER, A., ZSCHIESCHE, M., FRANKE, G., KNOKE, M., °ERTEL, R., FRITZ, P., VON RICHTER, O., WARZOK, R., HACHENBERG, T., KAUMANN, H.M., SCHRENK, D., TERHAAG, B., KROEMER, H. K. and SIEGMUND, W., 2000b, Induction of P-glycoprotein by rifampin increases intestinal secretion of talinolol in human beings: a new type of drug/drug interaction. Clinical Pharmacology and Therapeutics, 68, 345–355.
   Google Scholar
• WETTERICH, U., SPAHN-LANGGUTH, H., MUTSCHLER, E., TERHAAG, B., ROSCH, W. and LANGGUTH, P., 1996, Evidence for intestinal secretion as an additional clearance pathway of talinolol enantiomers: concentration and dose-dependent absorption in vitro and in vivo. Pharmaceutical Research, 13, 514–522.
   Google Scholar
• XIE, R., HAMMARLUND-UDENAES, M., DE BOER, A. G. and DE LANGE, E. C. M., 1999, The role of P-glycoprotein in blood-brain barrier transport of morphine: transcortical microdialysis studies in mdrla(-/-) and mdrl a( + / + ) mice. British Journal of Pharmacology, 128, 563–568.
   Google Scholar
• XIONG, H., TURNER, K. C., WARD, E. S., JANSEN, P. L. M. and BROUWER, K. L. R., 2000, Altered hepatobiliary disposition of acetaminophen glucuronide in isolated perfused livers from multidrug resistance-associated protein 2-deficient TR- rats. Journal of Pharmacology and Experimental Therapeutics, 295, 512–518.
   Google Scholar
• YAMANO, K., YAMAMOTO, K., KOTAKI, H., SAYURI, T., MATSUO, H., SAWADA, Y. and IGA, T., 1999, Correlation between in vivo and in vitro hepatic uptake of metabolic inhibitors of cytochrome P-450 in rats. Drug Metabolism and Disposition, 27, 1225–1231.
   PubMed Web of Science ®Google Scholar
• YAMANO, K., YAMAMOTO, K., KOTAKI, H., SAYURI, T., MATSU°, H., SAWADA, Y. and IGA, T., 2000, Quantitative prediction of metabolic inhibition of midazolam by erythromycin, diltiazem and verapamil in rats: implication of concentrative uptake of inhibitors into liver. Journal of Pharmacology and Therapeutics, 292, 1118–1126.
   Google Scholar
• YAMAZAKI, M., ÄKIYAMA, S., NISHIGAKI, R. and SUGIYAMA, Y., 1996a, Uptake is the rate-limiting step in overall hepatic elimination of pravastatin at steady-state in rats. Pharmaceutical Research, 13, 1559–1 564.
   Google Scholar
• YAMAZAKI, M., AKIYAMA, S., NIINUMA, K., NISHIGAKI, R. and SUGIYAMA, Y., 1997, Biliary excretion of pravastatin in rats: contribution of the excretion pathways mediated by the canalicular multispecific organic anion transporter Drug Metabolism and Disposition, 25, 1123–1129.
   Google Scholar
• YAMAZAKI, M., SUZUKI, H., HANANO, M., TOKUI, T., KOMAI, T. and SUGIYAMA, Y., 1993, Nat-independent multispecific anion transporter mediates active transport of pravastatin into rat liver. American Journal of Physiology, 27, G36–G44.
   Google Scholar
• YAMAZAKI, M., SUZUKI, H. and SUGIYAMA, Y., 1996b, Recent advances in carrier-mediated hepatic uptake and biliary excretion of xenobiotics. Pharmaceutical Research, 13, 497–513.
   PubMed Web of Science ®Google Scholar
• YOKOGAWA, K., TAKAHASHI, M., TAMAI, I., KONISHI, H., NOMURA, M., MORITANI, S., MIYAMOTO, K. and Tsup, A., 1999, P-glycoprotein-dependent disposition kinetics of tacrolirnus: studies in mdrla knockout mice. Pharmaceutical Research, 16, 1213–1218.
   PubMed Web of Science ®Google Scholar
• ZHANG, L., BRETT, C. M. and OIACOMINI, K. M., 1998a, Role of organic cation transporters in drug absorption and elimination. Annual Review of Pharmacology and Toxicology, 38, 431–460.
   PubMed Web of Science ®Google Scholar
• ZHANG, L., SCHANER, M. E. and OIACOMINI, K. M., 1998c, Functional characterisation of an organic cation transporter (hOCT1) in a transiently transfected human cell line. Journal of Pharmacology and Experimental Therapeutics, 286, 354–361.
   PubMed Web of Science ®Google Scholar
• ZHANG, Y., Guo, X., TIN, E. T. and BENET, L. Z., 1998b, Overlapping substrate specificities of cytochrome P450 3A and P-glycoprotein for a novel cysteine protease inhibitor. Drug Metabolism and Disposition, 26, 360–366.
   PubMed Web of Science ®Google Scholar
• ZONG, J. and PoiLacu, G. M., 2000, Morphine antinociception is enhanced in mdrla gene-deficient mice. Pharmaceutical Research, 17, 749–753.
   PubMed Web of Science ®Google Scholar