Effect of drug transporter genotypes on pravastatin disposition in European- and African-American participants

Objective Our aims were to evaluate the effects of polymorphisms in the hepatic drug uptake transporter organic anion transporting polypeptide 1B1 (OATP1B1, SLCO1B1) and eff lux transporters multidrug resistance-associated protein 2 (MRP2, ABCC2), bile salt export pump (BSER ABCB11), and breast cancer-related protein (BCRP, ABCG2) on single-dose pravastatin pharmacolkinetics in healthy European- and African-American participants. Methods The pharmacokinetics of a single oral 40mg 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 similar to 15% in European-Americans and similar to 1% in African-Americans. SLC01B1 521TC genotype was associated with significantly higher pravastatin area under the curve [AUC((0-5))] (P=0.01) and Crna. values (P<0.05). When analyzed by diplotype, SLCO1B1*1a/*15 (N=8) participants exhibited 45 and 80% higher AUC values than SLCO1B1*1a1*1a (N= 29) (P=0.013) and SLCO1B1*1b1*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 C-max 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 521 C or 388G variant allele, European-Americans demonstrated significantly higher pravastatin AUC and C-max values than African-Americans. Pharmacogenetics and Genomics 17:647-656 (C) 2007 Lippincott Williams & Wilkins.