High plasma pravastatin concentrations are associated with single nucleotide polymorphisms and haplotypes of organic anion transporting polypeptide-C (OATP-C, SLCO1B1)

Abstract

This study aimed to characterize possible relationships between polymorphisms in the drug transporter genes organic anion transporting polypeptide-C (OATP-C, SLCO1B1), OATP-B (SLCO2B1), multidrug resistance-associated protein 2 (MRP2, ABCC2) and multidrug resistance transporter (MDR1, ABCB1) and the pharmacokinetics of pravastatin. We studied 41 healthy Caucasian volunteers who had previously participated in pharmacokinetic studies with pravastatin. Six volunteers had a very high pravastatin AUC value and were defined as outliers according to statistical criteria. The OATP-C gene was sequenced completely in all subjects, and they were also genotyped for selected single nucleotide polymorphisms (SNP) in the OATP-B, MDR1 and MRP2 genes. Of the six outliers, five were heterozygous for the OATP-C 521T>C (Val174Ala) SNP (allele frequency 42%) and three were heterozygous for a new SNP in the promoter region of OATP-C (-11187G>A, allele frequency 25%). Among the remaining 35 subjects, two were homozygous and six were heterozygous carriers of the 521T>C SNP (allele frequency 14%, P = 0.0384 versus outliers) and three were heterozygous carriers of the -11187G>A SNP (allele frequency 4%, P = 0.0380 versus outliers). In subjects with the -11187GA or 521TC genotype, the mean pravastatin AUC0-12 was 98% (P = 0.0061) or 106% (P = 0.0034) higher, respectively, compared to subjects with the reference genotype. These results were substantiated by haplotype analysis. In heterozygous carriers of *15B (containing the 388A>G and 521T>C variants), the mean pravastatin AUC0-12 was 93% (P = 0.024) higher compared to non-carriers and, in heterozygous carriers of *17 (containing the -11187G>A, 388A>G and 521T>C variants), it was 130% (P = 0.0053) higher compared to non-carriers. No significant associations were found between OATP-B, MRP2 or MDR1 polymorphisms and the pharmacokinetics of pravastatin. These results suggest that haplotypes are more informative in predicting the OATP-C phenotype than single SNPs.

Pharmacokinetic interaction between pravastatin and olmesartan in relation to SLCO1B1 polymorphism

“…For urinary data, the mean Ae 0-24 and CLr 0-24 values of both pravastatin and RMS-416 were not markedly different between these groups (data not shown). It was somewhat unexpected that there were no significant differences in any pharmacokinetic parameters of pravastatin among SLCO1B1 genotypes, because previous studies provided accordant evidence that SLCO1B1*15 is associated with remarkably elevated plasma levels of pravastatin (Niemi et al 2004;Nishizato et al 2003). Because of the instability in acid conditions, pravastatin underwent acid-catalyzed conversion to form RMS-416 (3 0 a-isopravastatin) in the stomach after oral administration, and a considerable amount of RMS-416 was detectable in plasma, urine, and feces (Everett et al 1991).…”

“…Several single-nucleotide polymorphisms (SNPs) have been identified in SLCO1B1 (Nozawa et al 2002;Tirona et al 2001), and some are reported to be associated with alterations in the pharmacokinetics of certain substrate drugs, including repaglinide (Niemi et al 2005a), fexofenadine (Niemi et al 2005b), pitavastatin (Chung et al 2005;Ieiri et al 2007), and pravastatin (Mwinyi et al 2004;Niemi et al 2004;Nishizato et al 2003). Particularly subjects having SLCO1B1*15 allele (possessing both 388A [G and 521T[C) showed elevated systemic exposure of pravastatin as compared to subjects without this allele (Niemi et al 2004;Nishizato et al 2003). In contrast, some reports indicated that SLCO1B1*1b allele (possessing 388A [G) showed enhanced transport activity of OATP1B1 as compared with wild-type allele (i.e., *1a allele) (Maeda et al 2006;Mwinyi et al 2004).…”

Risk and preventive factors of low‐dose aspirin‐induced gastroduodenal injuries: A comprehensive review

“…The T521C SNP has been consistently linked with reduced transport activity of OATP1B1, both in vitro 54,[56][57][58] and in vivo. 53,59,60 The collective evidence indicates that statin blood concentrations are higher in subjects with the 521C allele, and a recent genome-wide study elucidated that the 521C allele is associated with an increased risk of simvastatin-induced myopathy. 61 Two haplotypes with nonsynonymous variations, *1b harboring A388G and *15 harboring A388G and T521C, have been frequently reported in Japanese, and the pravastatin blood concentration was significantly lower in *1b/*1b subjects than in *1a/*1a subjects.…”

“…[53][54][55] Among more than 40 mutations identified in SLCO1B, A388G (Asn130Asp) and T521C (Val174Ala) occur frequently and have been extensively investigated. The T521C SNP has been consistently linked with reduced transport activity of OATP1B1, both in vitro 54,[56][57][58] and in vivo.…”

Potential role of organic anion transporting polypeptide 1B1 (OATP1B1) in the selective hepatic uptake of hematoporphyrin monomethyl ether isomers

“…Compared with wild-type OATP1B1, c.521T>C was associated with increased systemic exposure to multiple drugs, including oral pravastatin [23,24] , fexofenadine [25] , and lopinavir [26,27] . In addition, the co-administration of OATP1B1 inhibitors may affect the pharmacokinetics of its substrates.…”