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

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 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 ~15% in European-Americans and ~1% in African-Americans. SLCO1B1 521TC genotype was associated with significantly higher pravastatin area under the curve [AUC (0)(1)(2)(3)(4)(5) NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript 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 521C or 388G variant allele, European-Americans demonstrated significantly higher pravastatin AUC and C max values than African-Americans.

The influence of SLCO1B1 (OATP1B1) gene polymorphisms on response to statin therapy

“…This suggests that both heterozygous (TC) and homozygous (CC) carriers of the c.521T4C substitution show decreased uptake of atorvastatin into the liver, resulting in increased plasma concentration. These findings are supported by Ho et al, 26 who investigated pravastatin. However, this did not hold true when Pasanen et al 18 Investigated rosuvastatin and found that although the CC genotype resulted in a significant increase in AUC (0À48 h) compared with TT (65%; P ¼ 0.002), only a strong trend was shown for TC versus TT (P ¼ 0.053).…”

“…3,[21][22][23] Similarly, in vitro studies of multidrug resistanceassociated protein 2 have shown that this protein transports a number of statins, 24 but in vivo pharmacogenomic evidence is inconclusive and limited to two small pharmacokinetic studies using pravastatin; these studies obtained contrasting results. 25,26 In contrast, the c.421C4A SNP in ABCG2 has been shown to alter the in vivo pharmacokinetics of both rosuvastatin 27,28 and atorvastatin, 27 although not pitavastatin 29 or pravastatin. 26 Both multidrug resistanceassociated protein 2 and breast cancer resistance protein are reviewed elsewhere by Ieiri et al 19 and although it is accepted that these and other transporters, both intestinal and hepatic, may play a role in statin disposition, this review will focus exclusively on OATP1B1, an hepatic influx transporter that is becoming increasing linked with differences in response to statin therapy.…”

“…25,26 In contrast, the c.421C4A SNP in ABCG2 has been shown to alter the in vivo pharmacokinetics of both rosuvastatin 27,28 and atorvastatin, 27 although not pitavastatin 29 or pravastatin. 26 Both multidrug resistanceassociated protein 2 and breast cancer resistance protein are reviewed elsewhere by Ieiri et al 19 and although it is accepted that these and other transporters, both intestinal and hepatic, may play a role in statin disposition, this review will focus exclusively on OATP1B1, an hepatic influx transporter that is becoming increasing linked with differences in response to statin therapy.…”

Association study between single-nucleotide polymorphisms in 199 drug-related genes and commonly measured quantitative traits of 752 healthy Japanese subjects

“…In addition to the UGT1A1 gene, recent studies have suggested the possible association of the adenosine triphosphate-binding cassette C2 (ABCC2) gene and the solute carrier organic anion transporter 1B1 (SLCO1B1) gene with serum bilirubin levels. [37][38][39] In our association study with serum total bilirubin levels, three SNPs within the ABCC2 gene (rs4148386, rs4148396 and rs2145852) and three SNPs within the SLCO1B1 gene (rs4149025, rs4149014 and rs4149018) showed P-values under 0.01, which were, however, far above the significance level after Bonferroni correction (data not shown). No genes except for UGT1A1 were clearly associated with serum total bilirubin levels.…”

CBR1 and CBR3 pharmacogenetics and their influence on doxorubicin disposition in Asian breast cancer patients

“…Association studies with polymorphic data from linked loci suggest that diplotype constitution, which characterizes the subset of every single-locus genotype in a gene and is representative of the type of chromosome pairs in an individual, (27,28) could be major determinants of phenotypes. (29) In the present study, homozygosity for the reference allele at the CBR1c.627C>T and +967G>A loci was observed to be associated with increased clearance and reduced exposure levels of doxorubicin in Asian breast cancer patients.…”