Abstract
This review illustrates the concept of a rate-determining process in the overall hepatic elimination of anionic drugs that involves transporters in the uptake process. A kinetic study in rats has demonstrated that uptake is the rate-determining process for most anionic drugs, and this is likely to hold true for the hepatic elimination of statins in humans. To simulate the effects of variations in the transporter activities on systemic and liver exposure, a physiologically based pharmacokinetic model was constructed for pravastatin, the overall elimination of which involves OATP1B1 and MRP2 in the hepatic uptake and canalicular efflux, respectively. The plasma concentrations of pravastatin in humans were successfully reproduced using the kinetic parameters extrapolated from in vitro data obtained using human hepatocytes and canalicular membrane vesicles and the scaling factors determined in rats. Sensitivity analyses showed that a variation in hepatic uptake altered the plasma concentration of pravastatin markedly, but had a small effect on the liver concentration, and vice versa for the canalicular efflux. Therefore, variation in the OATP1B1 activities will have small and large impacts on the therapeutic efficacy and adverse effect (myopathy) of pravastatin, respectively, whereas that affecting the MRP2 activities may have an opposite effect (i.e., large and small impacts on the therapeutic efficacy and side effect). This pharmacokinetic characteristics likely hold true for other anionic statins, i.e., variation of OATP1B1 is associated with the risk of adverse reactions, whereas that of sequestration mechanisms causes the variation of their pharmacological effect.
Similar content being viewed by others
References
Giacomini KM, Sugiyama Y (2005) Membrane transporters and drug response. In: Brunton LL, Lazo JS, Parker KL (eds) Goodman and Gilman’s the pharmacological basis of therapeutics, 11th edn. McGraw-Hill, New York, pp 41–70
Giacomini KM, Huang SM, Tweedie DJ, Benet LZ, Brouwer KL, Chu X, Dahlin A, Evers R, Fischer V, Hillgren KM, Hoffmaster KA, Ishikawa T, Keppler D, Kim RB, Lee CA, Niemi M, Polli JW, Sugiyama Y, Swaan PW, Ware JA, Wright SH, Yee SW, Zamek-Gliszczynski MJ, Zhang L (2010) Membrane transporters in drug development. Nat Rev Drug Discov 9:215–236
Nies AT, Schwab M, Keppler D (2008) Interplay of conjugating enzymes with OATP uptake transporters and ABCC/MRP efflux pumps in the elimination of drugs. Expert Opin Drug Metab Toxicol 4:545–568
Maeda K, Sugiyama Y (2008) Impact of genetic polymorphisms of transporters on the pharmacokinetic, pharmacodynamic and toxicological properties of anionic drugs. Drug Metab Pharmacokinet 23:223–235
Dobson PD, Kell DB (2008) Carrier-mediated cellular uptake of pharmaceutical drugs: an exception or the rule? Nat Rev Drug Discov 7:205–220
Klaassen CD, Aleksunes LM (2010) Xenobiotic, bile acid, and cholesterol transporters: function and regulation. Pharmacol Rev 62:1–96
Masereeuw R, Russel FG (2010) Therapeutic implications of renal anionic drug transporters. Pharmacol Ther 126:200–216
Matsushima S, Maeda K, Kondo C, Hirano M, Sasaki M, Suzuki H, Sugiyama Y (2005) Identification of the hepatic efflux transporters of organic anions using double-transfected Madin-Darby canine kidney II cells expressing human organic anion-transporting polypeptide 1B1 (OATP1B1)/multidrug resistance-associated protein 2, OATP1B1/multidrug resistance 1, and OATP1B1/breast cancer resistance protein. J Pharmacol Exp Ther 314:1059–1067
Sasaki M, Suzuki H, Ito K, Abe T, Sugiyama Y (2002) Transcellular transport of organic anions across a double-transfected Madin-Darby canine kidney II cell monolayer expressing both human organic anion-transporting polypeptide (OATP2/SLC21A6) and multidrug resistance-associated protein 2 (MRP2/ABCC2). J Biol Chem 277:6497–6503
Jacobsen W, Kuhn B, Soldner A, Kirchner G, Sewing KF, Kollman PA, Benet LZ, Christians U (2000) Lactonization is the critical first step in the disposition of the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor atorvastatin. Drug Metab Dispos 28:1369–1378
Lau YY, Huang Y, Frassetto L, Benet LZ (2007) Effect of OATP1B transporter inhibition on the pharmacokinetics of atorvastatin in healthy volunteers. Clin Pharmacol Ther 81:194–204
Shitara Y, Itoh T, Sato H, Li AP, Sugiyama Y (2003) Inhibition of transporter-mediated hepatic uptake as a mechanism for drug-drug interaction between cerivastatin and cyclosporin A. J Pharmacol Exp Ther 304:610–616
Niemi M, Backman JT, Kajosaari LI, Leathart JB, Neuvonen M, Daly AK, Eichelbaum M, Kivisto KT, Neuvonen PJ (2005) Polymorphic organic anion transporting polypeptide 1B1 is a major determinant of repaglinide pharmacokinetics. Clin Pharmacol Ther 77:468–478
Bidstrup TB, Bjornsdottir I, Sidelmann UG, Thomsen MS, Hansen KT (2003) CYP2C8 and CYP3A4 are the principal enzymes involved in the human in vitro biotransformation of the insulin secretagogue repaglinide. Br J Clin Pharmacol 56:305–314
Shitara Y, Sugiyama Y (2006) Pharmacokinetic and pharmacodynamic alterations of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors: drug-drug interactions and interindividual differences in transporter and metabolic enzyme functions. Pharmacol Ther 112:71–105
Rowland M, Benet LZ, Graham GG (1973) Clearance concepts in pharmacokinetics. J Pharmacokinet Biopharm 1:123–136
Pang KS, Rowland M (1977) Hepatic clearance of drugs. I. Theoretical considerations of a “well-stirred” model and a “parallel tube” model. Influence of hepatic blood flow, plasma and blood cell binding, and the hepatocellular enzymatic activity on hepatic drug clearance. J Pharmacokinet Biopharm 5:625–653
Pang KS, Rowland M (1977) Hepatic clearance of drugs. II. Experimental evidence for acceptance of the “well-stirred” model over the “parallel tube” model using lidocaine in the perfused rat liver in situ preparation. J Pharmacokinet Biopharm 5:655–680
Roberts MS, Rowland M (1986) A dispersion model of hepatic elimination: 1. Formulation of the model and bolus considerations. J Pharmacokinet Biopharm 14:227–260
Roberts MS, Rowland M (1986) A dispersion model of hepatic elimination: 2. Steady-state considerations–influence of hepatic blood flow, binding within blood, and hepatocellular enzyme activity. J Pharmacokinet Biopharm 14:261–288
Rowland M, Balant L, Peck C (2004) Physiologically based pharmacokinetics in drug development and regulatory science: a workshop report. Georgetown University, Washington, DC, May 29–30, 2002. AAPS PharmSci 6:E6
Kawai R, Lemaire M, Steimer JL, Bruelisauer A, Niederberger W, Rowland M (1994) Physiologically based pharmacokinetic study on a cyclosporin derivative, SDZ IMM 125. J Pharmacokinet Biopharm 22:327–365
Jones HM, Parrott N, Jorga K, Lave T (2006) A novel strategy for physiologically based predictions of human pharmacokinetics. Clin Pharmacokinet 45:511–542
Nakai D, Nakagomi R, Furuta Y, Tokui T, Abe T, Ikeda T, Nishimura K (2001) Human liver-specific organic anion transporter, LST-1, mediates uptake of pravastatin by human hepatocytes. J Pharmacol Exp Ther 297:861–867
Yamazaki M, Akiyama S, Ni’inuma K, Nishigaki R, Sugiyama Y (1997) Biliary excretion of pravastatin in rats: contribution of the excretion pathway mediated by canalicular multispecific organic anion transporter. Drug Metab Dispos 25:1123–1129
Muck W, Mai I, Fritsche L, Ochmann K, Rohde G, Unger S, Johne A, Bauer S, Budde K, Roots I, Neumayer HH, Kuhlmann J (1999) Increase in cerivastatin systemic exposure after single and multiple dosing in cyclosporine-treated kidney transplant recipients. Clin Pharmacol Ther 65:251–261
van Giersbergen PL, Treiber A, Schneiter R, Dietrich H, Dingemanse J (2007) Inhibitory and inductive effects of rifampin on the pharmacokinetics of bosentan in healthy subjects. Clin Pharmacol Ther 81:414–419
Zheng HX, Huang Y, Frassetto LA, Benet LZ (2009) Elucidating rifampin’s inducing and inhibiting effects on glyburide pharmacokinetics and blood glucose in healthy volunteers: unmasking the differential effects of enzyme induction and transporter inhibition for a drug and its primary metabolite. Clin Pharmacol Ther 85:78–85
Hirano M, Maeda K, Shitara Y, Sugiyama Y (2006) Drug-drug interaction between pitavastatin and various drugs via OATP1B1. Drug Metab Dispos 34:1229–1236
Matsushima S, Maeda K, Ishiguro N, Igarashi T, Sugiyama Y (2008) Investigation of the inhibitory effects of various drugs on the hepatic uptake of fexofenadine in humans. Drug Metab Dispos 36:663–669
Goodman LS, Gilman A (2006) The pharmacological basis of therapeutics, 11th edn. McGraw-Hill Publishers, New York
Ieiri I, Higuchi S, Sugiyama Y (2009) Genetic polymorphisms of uptake (OATP1B1, 1B3) and efflux (MRP2, BCRP) transporters: implications for inter-individual differences in the pharmacokinetics and pharmacodynamics of statins and other clinically relevant drugs. Expert Opin Drug Metab Toxicol 5:703–729
Kalliokoski A, Niemi M (2009) Impact of OATP transporters on pharmacokinetics. Br J Pharmacol 158:693–705
Nishizato Y, Ieiri I, Suzuki H, Kimura M, Kawabata K, Hirota T, Takane H, Irie S, Kusuhara H, Urasaki Y, Urae A, Higuchi S, Otsubo K, Sugiyama Y (2003) Polymorphisms of OATP-C (SLC21A6) and OAT3 (SLC22A8) genes: consequences for pravastatin pharmacokinetics. Clin Pharmacol Ther 73:554–565
Maeda K, Ieiri I, Yasuda K, Fujino A, Fujiwara H, Otsubo K, Hirano M, Watanabe T, Kitamura Y, Kusuhara H, Sugiyama Y (2006) Effects of organic anion transporting polypeptide 1B1 haplotype on pharmacokinetics of pravastatin. valsartan, and temocapril. Clin Pharmacol Ther 79:427–439
Iwai M, Suzuki H, Ieiri I, Otsubo K, Sugiyama Y (2004) Functional analysis of single nucleotide polymorphisms of hepatic organic anion transporter OATP1B1 (OATP-C). Pharmacogenetics 14:749–757
Kameyama Y, Yamashita K, Kobayashi K, Hosokawa M, Chiba K (2005) Functional characterization of SLCO1B1 (OATP-C) variants, SLCO1B1*5, SLCO1B1*15 and SLCO1B1*15 + C1007G, by using transient expression systems of HeLa and HEK293 cells. Pharmacogenet Genomics 15:513–522
Ho RH, Tirona RG, Leake BF, Glaeser H, Lee W, Lemke CJ, Wang Y, Kim RB (2006) Drug and bile acid transporters in rosuvastatin hepatic uptake: function, expression, and pharmacogenetics. Gastroenterology 130:1793–1806
Ueda K, Kato Y, Komatsu K, Sugiyama Y (2001) Inhibition of biliary excretion of methotrexate by probenecid in rats: quantitative prediction of interaction from in vitro data. J Pharmacol Exp Ther 297:1036–1043
Watanabe T, Kusuhara H, Maeda K, Shitara Y, Sugiyama Y (2009) Physiologically based pharmacokinetic modeling to predict transporter-mediated clearance and distribution of pravastatin in humans. J Pharmacol Exp Ther 328:652–662
Watanabe T, Kusuhara H, Maeda K, Kanamaru H, Saito Y, Hu Z, Sugiyama Y (2010) Investigation of the rate-determining process in the hepatic elimination of HMG-CoA reductase inhibitors in rats and humans. Drug Metab Dispos 38:215–222
Watanabe T, Maeda K, Kondo T, Nakayama H, Horita S, Kusuhara H, Sugiyama Y (2009) Prediction of the hepatic and renal clearance of transporter substrates in rats using in vitro uptake experiments. Drug Metab Dispos 37:1471–1479
Dingemanse J, van Giersbergen PL (2004) Clinical pharmacology of bosentan, a dual endothelin receptor antagonist. Clin Pharmacokinet 43:1089–1115
Kirchheiner J, Meineke I, Muller G, Bauer S, Rohde W, Meisel C, Roots I, Brockmoller J (2004) Influence of CYP2C9 and CYP2D6 polymorphisms on the pharmacokinetics of nateglinide in genotyped healthy volunteers. Clin Pharmacokinet 43:267–278
Zhang W, He YJ, Han CT, Liu ZQ, Li Q, Fan L, Tan ZR, Zhang WX, Yu BN, Wang D, Hu DL, Zhou HH (2006) Effect of SLCO1B1 genetic polymorphism on the pharmacokinetics of nateglinide. Br J Clin Pharmacol 62:567–572
Treiber A, Schneiter R, Hausler S, Stieger B (2007) Bosentan is a substrate of human OATP1B1 and OATP1B3: inhibition of hepatic uptake as the common mechanism of its interactions with cyclosporin A, rifampicin, and sildenafil. Drug Metab Dispos 35:1400–1407
Ishiguro N, Maeda K, Kishimoto W, Saito A, Harada A, Ebner T, Roth W, Igarashi T, Sugiyama Y (2006) Predominant contribution of OATP1B3 to the hepatic uptake of telmisartan, an angiotensin II receptor antagonist, in humans. Drug Metab Dispos 34:1109–1115
Stangier J, Schmid J, Turck D, Switek H, Verhagen A, Peeters PA, van Marle SP, Tamminga WJ, Sollie FA, Jonkman JH (2000) Absorption, metabolism, and excretion of intravenously and orally administered [14C]telmisartan in healthy volunteers. J Clin Pharmacol 40:1312–1322
Davies B, Morris T (1993) Physiological parameters in laboratory animals and humans. Pharm Res 10:1093–1095
Naritomi Y, Terashita S, Kimura S, Suzuki A, Kagayama A, Sugiyama Y (2001) Prediction of human hepatic clearance from in vivo animal experiments and in vitro metabolic studies with liver microsomes from animals and humans. Drug Metab Dispos 29:1316–1324
Iwatsubo T, Hirota N, Ooie T, Suzuki H, Shimada N, Chiba K, Ishizaki T, Green CE, Tyson CA, Sugiyama Y (1997) Prediction of in vivo drug metabolism in the human liver from in vitro metabolism data. Pharmacol Ther 73:147–171
Morimoto K, Oishi T, Ueda S, Ueda M, Hosokawa M, Chiba K (2004) A novel variant allele of OATP-C (SLCO1B1) found in a Japanese patient with pravastatin-induced myopathy. Drug Metab Pharmacokinet 19:453–455
Link E, Parish S, Armitage J, Bowman L, Heath S, Matsuda F, Gut I, Lathrop M, Collins R (2008) SLCO1B1 variants and statin-induced myopathy—a genomewide study. N Engl J Med 359:789–99
Singhvi SM, Pan HY, Morrison RA, Willard DA (1990) Disposition of pravastatin sodium, a tissue-selective HMG-CoA reductase inhibitor, in healthy subjects. Br J Clin Pharmacol 29:239–243
Takane H, Miyata M, Burioka N, Shigemasa C, Shimizu E, Otsubo K, Ieiri I (2006) Pharmacogenetic determinants of variability in lipid-lowering response to pravastatin therapy. J Hum Genet 51:822–826
Kivisto KT, Niemi M (2007) Influence of drug transporter polymorphisms on pravastatin pharmacokinetics in humans. Pharm Res 24:239–247
Igel M, Arnold KA, Niemi M, Hofmann U, Schwab M, Lutjohann D, von Bergmann K, Eichelbaum M, Kivisto KT (2006) Impact of the SLCO1B1 polymorphism on the pharmacokinetics and lipid-lowering efficacy of multiple-dose pravastatin. Clin Pharmacol Ther 79:419–426
Niemi M, Neuvonen PJ, Hofmann U, Backman JT, Schwab M, Lutjohann D, von Bergmann K, Eichelbaum M, Kivisto KT (2005) Acute effects of pravastatin on cholesterol synthesis are associated with SLCO1B1 (encoding OATP1B1) haplotype *17. Pharmacogenet Genomics 15:303–309
Naesens M, Kuypers DR, Verbeke K, Vanrenterghem Y (2006) Multidrug resistance protein 2 genetic polymorphisms influence mycophenolic acid exposure in renal allograft recipients. Transplantation 82:1074–1084
Rau T, Erney B, Gores R, Eschenhagen T, Beck J, Langer T (2006) High-dose methotrexate in pediatric acute lymphoblastic leukemia: impact of ABCC2 polymorphisms on plasma concentrations. Clin Pharmacol Ther 80:468–476
Kiyotani K, Mushiroda T, Kubo M, Zembutsu H, Sugiyama Y, Nakamura Y (2008) Association of genetic polymorphisms in SLCO1B3 and ABCC2 with docetaxel-induced leukopenia. Cancer Sci 99:967–972
Hirano M, Maeda K, Matsushima S, Nozaki Y, Kusuhara H, Sugiyama Y (2005) Involvement of BCRP (ABCG2) in the biliary excretion of pitavastatin. Mol Pharmacol 68:800–807
Kondo C, Suzuki H, Itoda M, Ozawa S, Sawada J, Kobayashi D, Ieiri I, Mine K, Ohtsubo K, Sugiyama Y (2004) Functional analysis of SNPs variants of BCRP/ABCG2. Pharm Res 21:1895–1903
Author information
Authors and Affiliations
Corresponding author
Additional information
This manuscript is from the symposium on the occasion of Professor Malcolm Rowland’s 70th birthday
Rights and permissions
About this article
Cite this article
Watanabe, T., Kusuhara, H. & Sugiyama, Y. Application of physiologically based pharmacokinetic modeling and clearance concept to drugs showing transporter-mediated distribution and clearance in humans. J Pharmacokinet Pharmacodyn 37, 575–590 (2010). https://doi.org/10.1007/s10928-010-9176-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10928-010-9176-y