Pharmaceutical Research

, Volume 24, Issue 2, pp 239–247 | Cite as

Influence of Drug Transporter Polymorphisms on Pravastatin Pharmacokinetics in Humans

Expert Review


The role of drug transporters in pravastatin disposition is underlined by the fact that pravastatin does not undergo significant cytochrome P-450 (CYP)-mediated biotransformation. The organic anion transporting polypeptide 1B1 (OATP1B1), encoded by SLCO1B1, and multidrug resistance-associated protein 2 [MRP2 (ABCC2)], are thought to be the major transporters involved in the pharmacokinetics of pravastatin in humans. Other transporters that may play a role include OATP2B1, organic anion transporter 3 (OAT3), bile salt export pump (BSEP), and the breast cancer resistance protein (BCRP). OATP1B1 and MRP2 mediate the hepatic uptake and biliary excretion of pravastatin, respectively. The SLCO1B1 and ABCC2 polymorphisms probably contribute to the high interindividual variability in pravastatin disposition. Recent small studies have characterized the impact of the SLCO1B1 polymorphism on pravastatin in humans, and especially the c.521T>C single-nucleotide polymorphism (SNP) seems to be an important determinant of pravastatin pharmacokinetics. Pravastatin plasma concentrations may be up to 100% higher in subjects carrying the c.521C variant, as found in the *5, *15, *16, and *17 haplotypes, reflecting diminished OATP1B1-mediated uptake into the major site of pravastatin elimination, the liver. The SLCO1B1 polymorphism seems to have a similar impact on the pharmacokinetics of single- and multiple-dose pravastatin. Overall, 2–5% of individuals in various populations may be expected to show markedly elevated plasma pravastatin concentrations due to the SLCO1B1 polymorphism. Of note, the impact of the SLCO1B1 polymorphism on statins may be dependent on ethnicity. Although individuals with a diminished hepatic uptake of pravastatin might be expected to show reduced cholesterol-lowering efficacy due to lower intracellular pravastatin concentrations, there is preliminary evidence to suggest that the SLCO1B1 polymorphism is not a major determinant of non-response to pravastatin. The possible consequences of drug transporter polymorphisms, especially the SLCO1B1 and ABCC2 polymorphisms, for the lipid-lowering efficacy and tolerability of pravastatin in various ethnic groups warrant further study.

Key words

drug disposition OATP pravastatin transporter vectorial transport 



area under the plasma concentration–time curve


breast cancer resistance protein


bile salt export pump


peak concentration in plasma


cytochrome P-450


3-hydroxy-3-methylglutaryl coenzyme A


low-density lipoprotein


multidrug resistance-associated protein


sodium-dependent taurocholate cotransporting polypeptide


organic anion transporter


organic anion transporting polypeptide


single-nucleotide polymorphism


  1. 1.
    S. M. Singhvi, H. Y. Pan, R. A. Morrison, and D. A. Willard. Disposition of pravastatin sodium, a tissue-selective HMG-CoA reductase inhibitor, in healthy subjects. Br. J. Clin. Pharmacol. 29:239–243 (1990).PubMedGoogle Scholar
  2. 2.
    T. Hatanaka. Clinical pharmacokinetics of pravastatin. Mechanisms of pharmacokinetic events. Clin. Pharmacokinet. 39:397–412 (2000).PubMedCrossRefGoogle Scholar
  3. 3.
    B. A. Hamelin and J. Turgeon. Hydrophilicity/lipophilicity: relevance for the pharmacology and clinical effects of HMG-CoA reductase inhibitors. Trends Pharmacol. Sci. 19:26–37 (1998).PubMedCrossRefGoogle Scholar
  4. 4.
    D. W. Everett, T. J. Chando, G. C. Didonato, S. M. Singhvi, H. Y. Pan, and S. H. Weinstein. Biotransformation of pravastatin sodium in humans. Drug Metab. Dispos. 19:740–748 (1991).PubMedGoogle Scholar
  5. 5.
    J. Triscari, D. O’Donnell, M. Zinny, and H. Y. Pan. Gastrointestinal absorption of pravastatin in healthy subjects. J. Clin. Pharmacol. 35:142–144 (1995).PubMedGoogle Scholar
  6. 6.
    D. Williams, and J. Feely. Pharmacokinetic–pharmacodynamic drug interactions with HMG-CoA reductase inhibitors. Clin. Pharmacokinet. 41:343–370 (2002).PubMedCrossRefGoogle Scholar
  7. 7.
    C. Transon, T. Leemann, and P. Dayer. In vitro comparative inhibition profiles of major human drug metabolising cytochrome P450 isozymes (CYP2C9, CYP2D6 and CYP3A4) by HMG-CoA reductase inhibitors. Eur. J. Clin. Pharmacol. 50:209–215 (1996).PubMedCrossRefGoogle Scholar
  8. 8.
    W. Jacobsen, G. Kirchner, K. Hallensleben, L. Mancinelli, M. Deters, I. Hackbarth, L. Z. Benet, K. F. Sewing, and U. Christians. Comparison of cytochrome P-450-dependent metabolism and drug interactions of the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors lovastatin and pravastatin in the liver. Drug Metab. Dispos. 27:173–179 (1999).PubMedGoogle Scholar
  9. 9.
    W. Jacobsen, G. Kirchner, K. Hallensleben, L. Mancinelli, M. Deters, I. Hackbarth, K. Baner, L. Z. Benet, K. F. Sewing, and U. Christians. Small intestinal metabolism of the 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor lovastatin and comparison with pravastatin. J. Pharmacol. Exp. Ther. 291:131–139 (1999).PubMedGoogle Scholar
  10. 10.
    P. J. Neuvonen, T. Kantola, and K. T. Kivistö. Simvastatin but not pravastatin is very susceptible to interaction with the CYP3A4 inhibitor itraconazole. Clin. Pharmacol. Ther. 63:332–341 (1998).PubMedCrossRefGoogle Scholar
  11. 11.
    T. Kantola, J. T. Backman, M. Niemi, K. T. Kivistö, and P. J. Neuvonen. Effect of fluconazole on plasma fluvastatin and pravastatin concentrations. Eur. J. Clin. Pharmacol. 56:225–229 (2000).PubMedCrossRefGoogle Scholar
  12. 12.
    B. Hsiang, Y. Zhu, Z. Wang, Y. Wu, V. Sasseville, W. P. Yang, and T. G. Kirchgessner. A novel human hepatic organic anion transporting polypeptide (OATP2). Identification of a liver-specific human organic anion transporting polypeptide and identification of rat and human hydroxymethylglutaryl-CoA reductase inhibitor trans-porters. J. Biol. Chem. 274:37161–37168 (1999).PubMedCrossRefGoogle Scholar
  13. 13.
    D. Nakai, R. Nakagomi, Y. Furuta, T. Tokui, T. Abe, T. Ikeda, and K. Nishimura. Human liver-specific organic anion transporter, LST-1, mediates uptake of pravastatin by human hepatocytes. J. Pharmacol. Exp. Ther. 297:861–867 (2001).PubMedGoogle Scholar
  14. 14.
    Y. Kameyama, K. Yamashita, K. Kobayashi, M. Hosokawa, and K. Chiba. 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 (2005).PubMedCrossRefGoogle Scholar
  15. 15.
    M. Yamazaki, S. Akiyama, K. Ni’Inuma, R. Nishigaki, and Y. Sugiyama. Biliary excretion of pravastatin in rats: contribution of the excretion pathway mediated by canalicular multispecific organic anion transporter (cMOAT). Drug Metab. Dispos. 25:1123–1129 (1997).PubMedGoogle Scholar
  16. 16.
    H. Fujino, D. Nakai, R. Nakagomi, M. Saito, T. Tokui, and J. Kojima. Metabolic stability and uptake by human hepatocytes of pitavastatin, a new inhibitor of HMG-CoA reductase. Arzneimittelforschung 54:382–388 (2004).PubMedGoogle Scholar
  17. 17.
    M. Hirano, K. Maeda, Y. Shitara, and Y. Sugiyama. Contribution of OATP2 (OATP1B1) and OATP8 (OATP1B3) to the hepatic uptake of pitavastatin in humans. J. Pharmacol. Exp. Ther. 311:139–146 (2004).PubMedCrossRefGoogle Scholar
  18. 18.
    R. B. Kim. 3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) and genetic variability (single nucleotide polymorphisms) in a hepatic drug uptake transporter: what’s it all about? Clin. Pharmacol. Ther. 75:381–385 (2004).PubMedCrossRefGoogle Scholar
  19. 19.
    S. G. Simonson, A. Raza, P. D. Martin, P. D. Mitchell, J. A. Jarcho, C. D. Brown, A. S. Windass, and D. W. Schneck. Rosuvastatin pharmacokinetics in heart transplant recipients administered an antirejection regimen including cyclosporine. Clin. Pharmacol. Ther. 76:167–177 (2004).PubMedCrossRefGoogle Scholar
  20. 20.
    R. H. Ho and R. B. Kim. Transporters and drug therapy: implications for drug disposition and disease. Clin. Pharmacol. Ther. 78:260–277 (2005).PubMedCrossRefGoogle Scholar
  21. 21.
    R. G. Tirona. Ethnic differences in statin disposition. Clin. Pharmacol. Ther. 78:311–316 (2005).PubMedCrossRefGoogle Scholar
  22. 22.
    J. König, Y. Cui, A. T. Nies, and D. Keppler. A novel human organic anion transporting polypeptide localized to the basolateral hepatocyte membrane. Am. J. Physiol.: Gastrointest. Liver Physiol. 278:G156–G164 (2000).Google Scholar
  23. 23.
    P. Chandra and K. L. Brouwer. The complexities of hepatic drug transport: current knowledge and emerging concepts. Pharm. Res. 21:719–735 (2004).PubMedCrossRefGoogle Scholar
  24. 24.
    K. Ito, H. Suzuki, T. Horie, and Y. Sugiyama. Apical/basolateral surface expression of drug transporters and its role in vectorial drug transport. Pharm. Res. 22:1559–1577 (2005).PubMedCrossRefGoogle Scholar
  25. 25.
    J. König, A. T. Nies, Y. Cui, I. Leier, and D. Keppler. Conjugate export pumps of the multidrug resistance protein (MRP) family: localization, substrate specificity, and MRP2-mediated drug resistance. Biochim. Biophys. Acta 1461:377–394 (1999).PubMedCrossRefGoogle Scholar
  26. 26.
    P. M. Gerk and M. Vore. Regulation of expression of the multidrug resistance-associated protein 2 (MRP2) and its role in drug disposition. J. Pharmacol. Exp. Ther. 302:407–415 (2002).PubMedCrossRefGoogle Scholar
  27. 27.
    D. Kobayashi, T. Nozawa, K. Imai, J. I. Nezu, A. Tsuji, and I. Tamai. Involvement of human organic anion transporting polypeptide OATP-B (SLC21A9) in pH-dependent transport across intestinal apical membrane. J. Pharmacol. Exp. Ther. 306:703–708 (2003).PubMedCrossRefGoogle Scholar
  28. 28.
    M. Takeda, R. Noshiro, M. L. Onozato, A. Tojo, H. Hasannejad, X. L. Huang, S. Narikawa, and H. Endou. Evidence for a role of human organic anion transporters in the muscular side effects of HMG-CoA reductase inhibitors. Eur. J. Pharmacol. 483:133–138 (2004).PubMedCrossRefGoogle Scholar
  29. 29.
    M. Hirano, K. Maeda, H. Hayashi, H. Kusuhara, and Y. Sugiyama. Bile salt export pump (BSEP/ABCB11) can transport a nonbile acid substrate, pravastatin. J. Pharmacol. Exp. Ther. 314:876–882 (2005).PubMedCrossRefGoogle Scholar
  30. 30.
    M. Hirano, K. Maeda, S. Matsushima, Y. Nozaki, H. Kusuhara, and Y. Sugiyama. Involvement of BCRP (ABCG2) in the biliary excretion of pitavastatin. Mol. Pharmacol. 68:800–807 (2005).PubMedGoogle Scholar
  31. 31.
    T. Gerloff, B. Stieger, B. Hagenbuch, J. Madon, L. Landmann, J. Roth, A. F. Hofmann, and P. J. Meier. The sister of P-glycoprotein represents the canalicular bile salt export pump of mammalian liver. J. Biol. Chem. 273:10046–10050 (1998).PubMedCrossRefGoogle Scholar
  32. 32.
    M. Maliepaard, G. L. Scheffer, I. F. Faneyte, M. A. van Gastelen, A. C. Pijnenborg, A. H. Schinkel, M. J. van De Vijver, R. J. Scheper, and J. H. Schellens. Subcellular localization and distribution of the breast cancer resistance protein transporter in normal human tissues. Cancer Res. 61:3458–3464 (2001).PubMedGoogle Scholar
  33. 33.
    K. Bogman, A. K. Peyer, M. Torok, E. Kusters, and J. Drewe. HMG-CoA reductase inhibitors and P-glycoprotein modulation. Br. J. Pharmacol. 132:1183–1192 (2001).PubMedCrossRefGoogle Scholar
  34. 34.
    E. Wang, C. N. Casciano, R. P. Clement, and W. W. Johnson. HMG-CoA reductase inhibitors (statins) characterized as direct inhibitors of P-glycoprotein. Pharm. Res. 18:800–806 (2001).PubMedCrossRefGoogle Scholar
  35. 35.
    C. Chen, R. J. Mireles, S. D. Campbell, J. Lin, J. B. Mills, J. J. Xu, and T. A. Smolarek. Differential interaction of 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors with ABCB1, ABCC2, and OATP1B1. Drug Metab. Dispos. 33:537–546 (2005).PubMedCrossRefGoogle Scholar
  36. 36.
    S. Matsushima, K. Maeda, C. Kondo, M. Hirano, M. Sasaki, H. Suzuki, and Y. Sugiyama. 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 (2005).PubMedCrossRefGoogle Scholar
  37. 37.
    Y. Shitara, T. Itoh, H. Sato, A. P. Li, and Y. Sugiyama. 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 (2003).PubMedCrossRefGoogle Scholar
  38. 38.
    W. Mück, I. Mai, L. Fritsche, K. Ochmann, G. Rohde, S. Unger, A. Johne, S. Bauer, K. Budde, I. Roots, H. H. Neumayer, and J. Kuhlmann. Increase in cerivastatin systemic exposure after single and multiple dosing in cyclosporine-treated kidney transplant recipients. Clin. Pharmacol. Ther. 65:251–261 (1999).PubMedCrossRefGoogle Scholar
  39. 39.
    M. Hedman, P. J. Neuvonen, M. Neuvonen, C. Holmberg, and M. Antikainen. Pharmacokinetics and pharmacodynamics of pravastatin in pediatric and adolescent cardiac transplant recipients on a regimen of triple immunosuppression. Clin. Pharmacol. Ther. 75:101–109 (2004).PubMedCrossRefGoogle Scholar
  40. 40.
    M. Hermann, A. Åsberg, H. Christensen, H. Holdaas, A. Hartmann, and J. L. Reubsaet. Substantially elevated levels of atorvastatin and metabolites in cyclosporine-treated renal transplant recipients. Clin. Pharmacol. Ther. 76:388–391 (2004).PubMedCrossRefGoogle Scholar
  41. 41.
    I. Tamai and A. R. Safa. Competitive interaction of cyclosporins with the Vinca alkaloid-binding site of P-glycoprotein in multidrug-resistant cells. J. Biol. Chem. 265:16509–16513 (1990).PubMedGoogle Scholar
  42. 42.
    Z. S. Chen, T. Kawabe, M. Ono, S. Aoki, T. Sumizawa, T. Furukawa, T. Uchiumi, M. Wada, M. Kuwano, and S. I. Akiyama. Effect of multidrug resistance-reversing agents on transporting activity of human canalicular multispecific organic anion transporter. Mol. Pharmacol. 56:1219–1228 (1999).PubMedGoogle Scholar
  43. 43.
    M. Yamazaki, S. Akiyama, R. Nishigaki, and Y. Sugiyama. Uptake is the rate-limiting step in the overall hepatic elimination of pravastatin at steady-state in rats. Pharm. Res. 13:1559–1564 (1996).PubMedCrossRefGoogle Scholar
  44. 44.
    R. H. Ho, R. G. Tirona, B. F. Leake, H. Glaeser, W. Lee, C. J. Lemke, Y. Wang, and R. B. Kim. Drug and bile acid transporters in rosuvastatin hepatic uptake: function, expression, and pharmacogenetics. Gastroenterology 130:1793–1806 (2006).PubMedCrossRefGoogle Scholar
  45. 45.
    Y. Nishizato, I. Ieiri, H. Suzuki, M. Kimura, K. Kawabata, T. Hirota, H. Takane, S. Irie, H. Kusuhara, Y. Urasaki, A. Urae, S. Higuchi, K. Otsubo, and Y. Sugiyama. Polymorphisms of OATP-C (SLC21A6) and OAT3 (SLC22A8) genes: consequences for pravastatin pharmacokinetics. Clin. Pharmacol. Ther. 73:554–565 (2003).PubMedCrossRefGoogle Scholar
  46. 46.
    J. Mwinyi, A. Johne, S. Bauer, I. Roots, and T. Gerloff. Evidence for inverse effects of OATP-C (SLC21A6) *5 and *1b haplotypes on pravastatin kinetics. Clin. Pharmacol. Ther. 75:415–421 (2004).PubMedCrossRefGoogle Scholar
  47. 47.
    M. Niemi, E. Schaeffeler, T. Lang, M. F. Fromm, M. Neuvonen, C. Kyrklund, J. T. Backman, R. Kerb, M. Schwab, P. J. Neuvonen, M. Eichelbaum, and K. T. Kivistö. High plasma pravastatin concentrations are associated with single nucleotide polymorphisms and haplotypes of organic anion transporting polypeptide-C (OATP-C, SLCO1B1). Pharmacogenetics 14:429–440 (2004).PubMedCrossRefGoogle Scholar
  48. 48.
    M. Niemi, P. J. Neuvonen, U. Hofmann, J. T. Backman, M. Schwab, D. Lütjohann, K. von Bergmann, M. Eichelbaum, and K. T. Kivistö. Acute effects of pravastatin on cholesterol synthesis are associated with SLCO1B1 (encoding OATP1B1) haplotype *17. Pharmacogenet. Genomics 15:303–309 (2005).PubMedCrossRefGoogle Scholar
  49. 49.
    M. K. Pasanen, J. T. Backman, P. J. Neuvonen, and M. Niemi. Frequencies of single nucleotide polymorphisms and haplotypes of organic anion transporting polypeptide 1B1 (SLCO1B1) gene in a Finnish population. Eur. J. Clin. Pharmacol. 62:409–415 (2006).PubMedCrossRefGoogle Scholar
  50. 50.
    J. Y. Chung, J. Y. Cho, K. S. Yu, J. R. Kim, D. S. Oh, H. R. Jung, K. S. Lim, K. H. Moon, S. G. Shin, and I. J. Jang. Effect of OATP1B1 (SLCO1B1) variant alleles on the pharmacokinetics of pitavastatin in healthy volunteers. Clin. Pharmacol. Ther. 78:342–350 (2005).PubMedCrossRefGoogle Scholar
  51. 51.
    E. Lee, S. Ryan, B. Birmingham, J. Zalikowski, R. March, H. Ambrose, R. Moore, C. Lee, Y. Chen, and D. Schneck. Rosuvastatin pharmacokinetics and pharmacogenetics in white and Asian subjects residing in the same environment. Clin. Pharmacol. Ther. 78:330–341 (2005).PubMedCrossRefGoogle Scholar
  52. 52.
    R. G. Tirona, B. F. Leake, G. Merino, and R. B. Kim. Polymorphisms in OATP-C: identification of multiple allelic variants associated with altered transport activity among European- and African-Americans. J. Biol. Chem. 276:35669–35675 (2001).PubMedCrossRefGoogle Scholar
  53. 53.
    R. G. Tirona, B. F. Leake, A. W. Wolkoff, and R. B. Kim. Human organic anion transporting polypeptide-C (SLC21A6) is a major determinant of rifampin-mediated pregnane X receptor activation. J. Pharmacol. Exp. Ther. 304:223–228 (2003).PubMedCrossRefGoogle Scholar
  54. 54.
    T. Nozawa, H. Minami, S. Sugiura, A. Tsuji, and I. Tamai. Role of organic anion transporter OATP1B1 (OATP-C) in hepatic uptake of irinotecan and its active metabolite, 7-ethyl-10-hydroxycamptothecin: in vitro evidence and effect of single nucleotide polymorphisms. Drug Metab. Dispos. 33:434–439 (2005).PubMedCrossRefGoogle Scholar
  55. 55.
    M. Niemi, J. T. Backman, L. I. Kajosaari, J. B. Leathart, M. Neuvonen, A. K. Daly, M. Eichelbaum, K. T. Kivistö, and P. J. Neuvonen. Polymorphic organic anion transporting polypeptide 1B1 is a major determinant of repaglinide pharmacokinetics. Clin. Pharmacol. Ther. 77:468–478 (2005).PubMedCrossRefGoogle Scholar
  56. 56.
    T. Nozawa, M. Nakajima, I. Tamai, K. Noda, J. I. Nezu, Y. Sai, A. Tsuji, and T. Yokoi. Genetic polymorphisms of human organic anion transporters OATP-C (SLC21A6) and OATP-B (SLC21A9): allele frequencies in the Japanese population and functional analysis. J. Pharmacol. Exp. Ther. 302:804–813 (2002).PubMedCrossRefGoogle Scholar
  57. 57.
    C. Michalski, Y. Cui, A. T. Nies, A. K. Nuessler, P. Neuhaus, U. M. Zanger, K. Klein, M. Eichelbaum, D. Keppler, and J. König. A naturally occurring mutation in the SLC21A6 gene causing impaired membrane localization of the hepatocyte uptake transporter. J. Biol. Chem. 277:43058–43063 (2002).PubMedCrossRefGoogle Scholar
  58. 58.
    M. Iwai, H. Suzuki, I. Ieiri, K. Otsubo, and Y. Sugiyama. Functional analysis of single nucleotide polymorphisms of hepatic organic anion transporter OATP1B1 (OATP-C). Pharmacogenetics 14:749–757 (2004)PubMedCrossRefGoogle Scholar
  59. 59.
    K. Maeda, I. Ieiri, K. Yasuda, A. Fujino, H. Fujiwara, K. Otsubo, M. Hirano, T. Watanabe, Y. Kitamura, H. Kusuhara, and Y. Sugiyama. Effects of organic anion transporting polypeptide 1B1 haplotype on pharmacokinetics of pravastatin, valsartan, and temocapril. Clin. Pharmacol. Ther. 79:427–439 (2006).PubMedCrossRefGoogle Scholar
  60. 60.
    M. Igel, K. A. Arnold, M. Niemi, U. Hofmann, M. Schwab, D. Lütjohann, K. von Bergmann, M. Eichelbaum, and K. T. Kivistö. Impact of the SLCO1B1 polymorphism on the pharmacokinetics and lipid-lowering efficacy of multiple-dose pravastatin. Clin. Pharmacol. Ther. 79:419–426 (2006).PubMedCrossRefGoogle Scholar
  61. 61.
    M. Sasaki, H. Suzuki, K. Ito, T. Abe, and Y. Sugiyama. 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 (2002).PubMedCrossRefGoogle Scholar
  62. 62.
    S. Toh, M. Wada, T. Uchiumi, A. Inokuchi, Y. Makino, Y. Horie, Y. Adachi, S. Sakisaka, and M. Kuwano. Genomic structure of the canalicular multispecific organic anion-transporter gene (MRP2/cMOAT) and mutations in the ATP-binding-cassette region in Dubin–Johnson syndrome. Am. J. Hum. Genet. 64:739–746 (1999).PubMedCrossRefGoogle Scholar
  63. 63.
    K. T. Kivistö, O. Grisk, U. Hofmann, K. Meissner, K. U. Möritz, C. Ritter, K. A. Arnold, D. Lütjohann, K. von Bergmann, I. Klöting, M. Eichelbaum, and H. K. Kroemer. Disposition of oral and intravenous pravastatin in Mrp2-deficient TR- rats. Drug Metab. Dispos. 33:1593–1596 (2005).PubMedCrossRefGoogle Scholar
  64. 64.
    M. Niemi, K. A. Arnold, J. T. Backman, M. K. Pasanen, U. Gödtel-Armbrust, L. Wojnowski, U. M. Zanger, P. J. Neuvonen, M. Eichelbaum, K. T. Kivistö, and T. Lang. Association of genetic polymorphism in ABCC2 with hepatic MRP2 expression and pravastatin pharmacokinetics. Pharmacogenet. Genomics (2006) (in press).Google Scholar
  65. 65.
    C. Marzolini, E. Paus, T. Buclin, and R. B. Kim. Polymorphisms in human MDR1 (P-glycoprotein): recent advances and clinical relevance. Clin. Pharmacol. Ther. 75:13–33 (2004).PubMedCrossRefGoogle Scholar
  66. 66.
    W. Zhang, B. N. Yu, Y. J. He, L. Fan, Q. Li, Z. Q. Liu, A. Wang, Y. L. Liu, Z. R. Tan, Fen-Jiang, Y. F. Huang, and H. H. Zhou. Role of BCRP 421C>A polymorphism on rosuvastatin pharmacokinetics in healthy Chinese males. Clin Chim Acta 373:99–103 (2006).PubMedCrossRefGoogle Scholar
  67. 67.
    K. Kajinami, N. Takekoshi, M. E. Brousseau, and E. J. Schaefer. Pharmacogenetics of HMG-CoA reductase inhibitors: exploring the potential for genotype-based individualization of coronary heart disease management. Atherosclerosis 177:219–234 (2004).PubMedCrossRefGoogle Scholar
  68. 68.
    A. H. Maitland-van der Zee and E. Boerwinkle. Pharmacogenetics of response to statins: where do we stand? Curr. Atheroscler. Rep. 7:204–208 (2005).PubMedCrossRefGoogle Scholar
  69. 69.
    I. Zineh. HMG-CoA reductase inhibitor pharmacogenomics: overview and implications for practice. Future Cardiol. 1:191–206 (2005).PubMedCrossRefGoogle Scholar
  70. 70.
    F. Pazzucconi, F. Dorigotti, G. Gianfranceschi, G. Campagnoli, M. Sirtori, G. Franceschini, and C. R. Sirtori. Therapy with HMG CoA reductase inhibitors: characteristics of the long term permanence of hypocholesterolemic activity. Atherosclerosis 117:189–198 (1995).PubMedCrossRefGoogle Scholar
  71. 71.
    D. I. Chasman, D. Posada, L. Subrahmanyan, N. R. Cook, V. P. Stanton Jr, and P. M. Ridker. Pharmacogenetic study of statin therapy and cholesterol reduction. J. Am. Assoc. Med. 291:2821–2827 (2004).CrossRefGoogle Scholar
  72. 72.
    J. F. Thompson, M. Man, K. J. Johnson, L. S. Wood, M. E. Lira, D. B. Lloyd, P. Banerjee, P. M. Milos, S. P. Myrand, J. Paulauskis, M. A. Milad, and W. J. Sasiela. An association study of 43 SNPs in 16 candidate genes with atorvastatin response. Pharmacogenomics J 5:352–358 (2005).PubMedCrossRefGoogle Scholar
  73. 73.
    R. H. Knopp. Drug treatment of lipid disorders. N. Engl. J. Med. 341:498–511 (1999).PubMedCrossRefGoogle Scholar
  74. 74.
    J. A. Tobert. Lovastatin and beyond: the history of the HMG-CoA reductase inhibitors. Nat. Rev. Drug Discov. 2:517–526 (2003).PubMedCrossRefGoogle Scholar
  75. 75.
    P. H. Jones, J. A. Farmer, M. D. Cressman, J. M. McKenney, J. T. Wright, J. D. Proctor, D. M. Berkson, D. J. Farnham, P. M. Wolfson, and H. T. Colfer. Once-daily pravastatin in patients with primary hypercholesterolemia: a dose–response study. Clin. Cardiol. 14:146–151 (1991).PubMedCrossRefGoogle Scholar
  76. 76.
    D. R. Illingworth, D. W. Erkelens, U. Keller, G. R. Thompson, and M. J. Tikkanen. Defined daily doses in relation to hypolipidaemic efficacy of lovastatin, pravastatin, and simvastatin. Lancet 343:1554–1555 (1994).PubMedCrossRefGoogle Scholar
  77. 77.
    S. Marshall, P. A. Meredith, and H. L. Elliott. Efficacy of low-density-lipoprotein lowering with statins. Lancet 344:684 (1994).PubMedCrossRefGoogle Scholar
  78. 78.
    E. Reihner, M. Rudling, D. Stahlberg, L. Berglund, S. Ewerth, I. Björkhem, K. Einarsson, and B. Angelin. Influence of pravastatin, a specific inhibitor of HMG-CoA reductase, on hepatic metabolism of cholesterol. N. Engl. J. Med. 323:224–228 (1990).PubMedCrossRefGoogle Scholar
  79. 79.
    D. D. Cilla Jr, L. R. Whitfield, D. M. Gibson, A. J. Sedman, and E. L. Posvar. Multiple-dose pharmacokinetics, pharmacodynamics, and safety of atorvastatin, an inhibitor of HMG-CoA reductase, in healthy subjects. Clin. Pharmacol. Ther. 60:687–695 (1996).PubMedCrossRefGoogle Scholar
  80. 80.
    T. A. Miettinen, H. Gylling, N. Lindbohm, T. E. Miettinen, R. A. Rajaratnam, and H. Relas. Finnish Treat-to-Target Study Investigators. Serum noncholesterol sterols during inhibition of cholesterol synthesis by statins. J. Lab. Clin. Med. 141:131–137 (2003).PubMedCrossRefGoogle Scholar
  81. 81.
    R. Tachibana-Iimori, Y. Tabara, H. Kusuhara, K. Kohara, R. Kawamoto, J. Nakura, K. Tokunaga, I. Kondo, Y. Sugiyama, and T. Miki. Effect of genetic polymorphism of OATP-C (SLCO1B1) on lipid-lowering response to HMG-CoA reductase inhibitors. Drug Metab. Pharmacokinet. 19:375–380 (2004).PubMedCrossRefGoogle Scholar
  82. 82.
    M. A. Pfeffer, A. Keech, F. M. Sacks, S. M. Cobbe, A. Tonkin, R. P. Byington, B. R. Davis, C. P. Friedman, and E. Braunwald. Safety and tolerability of pravastatin in long-term clinical trials: prospective Pravastatin Pooling (PPP) Project. Circulation 105:2341–2346 (2002).PubMedCrossRefGoogle Scholar
  83. 83.
    P. D. Thompson, P. Clarkson, and R. H. Karas. Statin-associated myopathy. J. Am. Assoc. Med. 289:1681–1690 (2003).CrossRefGoogle Scholar
  84. 84.
    K. Morimoto, T. Oishi, S. Ueda, M. Ueda, M. Hosokawa, and K. Chiba. A novel variant allele of OATP-C (SLCO1B1) found in a Japanese patient with pravastatin-induced myopathy. Drug Metab. Pharmacokinet. 19:453–455 (2004).PubMedCrossRefGoogle Scholar
  85. 85.
    I. Björkhem, T. Miettinen, E. Reihner, S. Ewerth, B. Angelin, and K. Einarsson. Correlation between serum levels of some cholesterol precursors and activity of HMG-CoA reductase in human liver. J. Lipid Res. 28:1137–1143 (1987).PubMedGoogle Scholar
  86. 86.
    H. J. Kempen, J. F. Glatz, J. A. Gevers Leuven, H. A. van der Voort, and M. B. Katan. Serum lathosterol concentration is an indicator of whole-body cholesterol synthesis in humans. J. Lipid Res. 29:1149–1155 (1988).PubMedGoogle Scholar
  87. 87.
    T. A. Miettinen, R. S. Tilvis, and Y. A. Kesäniemi. Serum plant sterols and cholesterol precursors reflect cholesterol absorption and synthesis in volunteers of a randomly selected male population. Am. J. Epidemiol. 131:20–31 (1990).PubMedGoogle Scholar

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© Springer Science+Business Media, LLC 2006

Authors and Affiliations

  1. 1.Department of Pharmacological Sciences, Medical SchoolUniversity of TampereTampereFinland
  2. 2.Department of Clinical PharmacologyUniversity of Helsinki and Helsinki University Central HospitalHelsinkiFinland

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