Effect of Drug Transporter Genotypes on Pravastatin Disposition in European- and African-American Participants

Overview

Journal Pharmacogenet Genomics

Specialties Genetics
Pharmacology

Date 2007 Jul 12

PMID 17622941

Citations 65

Authors

Richard H Ho

Leena Choi

Wooin Lee

Gail Mayo

Ute I Schwarz

Rommel G Tirona

David G Bailey

C Michael Stein

Richard B Kim

Affiliations

Soon will be listed here.

Abstract

Objective: Our aims were to evaluate the effects of polymorphisms in the hepatic drug uptake transporter organic anion transporting polypeptide 1B1 (OATP1B1, SLCO1B1) and efflux transporters multidrug resistance-associated protein 2 (MRP2, ABCC2), bile salt export pump (BSEP, ABCB11), and breast cancer-related protein (BCRP, ABCG2) on single-dose pravastatin pharmacokinetics in healthy European- and African-American participants.

Methods: The pharmacokinetics of a single oral 40 mg dose of pravastatin was determined in 107 participants (69 European-Americans and 38 African-Americans). Participants were genotyped for known OATP1B1, MRP2, BSEP, and BCRP polymorphisms. Baseline serum total and unconjugated plasma bilirubin concentrations were also determined.

Results: OATP1B1 genotypes were ethnicity-dependent with a 521C allele frequency of approximately 15% in European-Americans and approximately 1% in African-Americans. SLCO1B1 521TC genotype was associated with significantly higher pravastatin area under the curve [AUC(0-5)] (P=0.01) and Cmax values (P<0.05). When analyzed by diplotype, SLCO1B1*1a/*15 (N=8) participants exhibited 45 and 80% higher AUC values than SLCO1B1*1a/*1a (N=29) (P=0.013) and SLCO1B1*1b/*1b (N=34) (P=0.001) carriers, respectively. SLCO1B1*15/*15 (N=2) participants exhibited 92 and 149% higher AUC values than SLCO1B1*1a/*1a (P=0.017) and SLCO1B1*1b/*1b (P=0.011) carriers, respectively. European-Americans had significantly higher plasma pravastatin AUC(0-5) (P=0.01) and Cmax values (P=0.009) than African-Americans. Neither ABCC2, ABCB11, nor ABCG2 genotypes were associated with differences in pravastatin pharmacokinetics. We did not observe an effect of SLCO1B1 genotype on baseline total or unconjugated bilirubin levels.

Conclusion: SLCO1B1 genotype, in particular the 521C allele, had a significant effect on the pharmacokinetics of pravastatin. Even when adjusted for the presence of the SLCO1B1 521C or 388G variant allele, European-Americans demonstrated significantly higher pravastatin AUC and Cmax values than African-Americans.

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References

Ieiri I, Suzuki H, Kimura M, Takane H, Nishizato Y, Irie S . Influence of common variants in the pharmacokinetic genes (OATP-C, UGT1A1, and MRP2) on serum bilirubin levels in healthy subjects. Hepatol Res. 2004; 30(2):91-95. DOI: 10.1016/j.hepres.2004.07.005. View

Morisaki K, Robey R, Ozvegy-Laczka C, Honjo Y, Polgar O, Steadman K . Single nucleotide polymorphisms modify the transporter activity of ABCG2. Cancer Chemother Pharmacol. 2005; 56(2):161-72. DOI: 10.1007/s00280-004-0931-x. View

Hsiang B, Zhu Y, Wang Z, Wu Y, Sasseville V, Yang W . 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 transporters. J Biol Chem. 1999; 274(52):37161-8. DOI: 10.1074/jbc.274.52.37161. View

Hatanaka T . Clinical pharmacokinetics of pravastatin: mechanisms of pharmacokinetic events. Clin Pharmacokinet. 2001; 39(6):397-412. DOI: 10.2165/00003088-200039060-00002. View

Hirouchi M, Suzuki H, Itoda M, Ozawa S, Sawada J, Ieiri I . Characterization of the cellular localization, expression level, and function of SNP variants of MRP2/ABCC2. Pharm Res. 2004; 21(5):742-8. DOI: 10.1023/b:pham.0000026422.06207.33. View

Kivisto K, Grisk O, Hofmann U, Meissner K, Moritz K, Ritter C . Disposition of oral and intravenous pravastatin in MRP2-deficient TR- rats. Drug Metab Dispos. 2005; 33(11):1593-6. DOI: 10.1124/dmd.105.006262. View

Nakai D, Nakagomi R, Furuta Y, Tokui T, Abe T, Ikeda T . Human liver-specific organic anion transporter, LST-1, mediates uptake of pravastatin by human hepatocytes. J Pharmacol Exp Ther. 2001; 297(3):861-7. View

Siekmeier R, Gross W, Marz W . Determination of pravastatin by high performance liquid chromatography. Int J Clin Pharmacol Ther. 2000; 38(9):419-25. DOI: 10.5414/cpp38419. View

Ho R, Kim R . Transporters and drug therapy: implications for drug disposition and disease. Clin Pharmacol Ther. 2005; 78(3):260-77. DOI: 10.1016/j.clpt.2005.05.011. View

10.

Nishizato Y, Ieiri I, Suzuki H, Kimura M, Kawabata K, Hirota T . Polymorphisms of OATP-C (SLC21A6) and OAT3 (SLC22A8) genes: consequences for pravastatin pharmacokinetics. Clin Pharmacol Ther. 2003; 73(6):554-65. DOI: 10.1016/S0009-9236(03)00060-2. View

11.

Livak K . SNP genotyping by the 5'-nuclease reaction. Methods Mol Biol. 2002; 212:129-47. DOI: 10.1385/1-59259-327-5:129. View

12.

Wang P, Kim R, Chowdhury J, Wolkoff A . The human organic anion transport protein SLC21A6 is not sufficient for bilirubin transport. J Biol Chem. 2003; 278(23):20695-9. DOI: 10.1074/jbc.M301100200. View

13.

Nozawa T, Nakajima M, Tamai I, Noda K, Nezu J, Sai Y . 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. 2002; 302(2):804-13. DOI: 10.1124/jpet.302.2.804. View

14.

Tirona R, Leake B, Merino G, Kim R . Polymorphisms in OATP-C: identification of multiple allelic variants associated with altered transport activity among European- and African-Americans. J Biol Chem. 2001; 276(38):35669-75. DOI: 10.1074/jbc.M103792200. View

15.

Eloranta M, Hakli T, Hiltunen M, Helisalmi S, Punnonen K, Heinonen S . Association of single nucleotide polymorphisms of the bile salt export pump gene with intrahepatic cholestasis of pregnancy. Scand J Gastroenterol. 2003; 38(6):648-52. DOI: 10.1080/00365520310000807. View

16.

Marzolini C, Tirona R, Kim R . Pharmacogenomics of the OATP and OAT families. Pharmacogenomics. 2004; 5(3):273-82. DOI: 10.1517/phgs.5.3.273.29831. View

17.

Cui Y, Konig J, Leier I, Buchholz U, Keppler D . Hepatic uptake of bilirubin and its conjugates by the human organic anion transporter SLC21A6. J Biol Chem. 2001; 276(13):9626-30. DOI: 10.1074/jbc.M004968200. View

18.

Lee E, Ryan S, Birmingham B, Zalikowski J, March R, Ambrose H . Rosuvastatin pharmacokinetics and pharmacogenetics in white and Asian subjects residing in the same environment. Clin Pharmacol Ther. 2005; 78(4):330-41. DOI: 10.1016/j.clpt.2005.06.013. View

19.

Meier Y, Pauli-Magnus C, Zanger U, Klein K, Schaeffeler E, Nussler A . Interindividual variability of canalicular ATP-binding-cassette (ABC)-transporter expression in human liver. Hepatology. 2006; 44(1):62-74. DOI: 10.1002/hep.21214. View

20.

Hirano M, Maeda K, Matsushima S, Nozaki Y, Kusuhara H, Sugiyama Y . Involvement of BCRP (ABCG2) in the biliary excretion of pitavastatin. Mol Pharmacol. 2005; 68(3):800-7. DOI: 10.1124/mol.105.014019. View