Evidence for inverse effects of OATP-C (SLC21A6) *5 and *1b haplotypes on pravastatin kinetics

Objective: We compared the pharmacogenetic effects of OATP-C (organic anion transporting polypeptide C) *1a, *1b (A388G), and *5 (T521C) haplotypes on single-dose pharmacokinetics of pravastatin in white subjects. Methods: Thirty healthy white male subjects were grouped according to their OATP-Chaplotype. Each group contained 10 individuals who were either homozygous or heterozygous carriers of the *1a, *1b, or *5 haplotype. After a single oral dose of 40 mg pravastatin, we analyzed kinetic parameters of pravastatin disposition. Results: Values for the area under the plasma concentration-time curve from time 0 to 6 hours [AUC(0-6)] in *1a/*1a, *1a/*1bor *1b/*1b, and *1a/*5individuals were 114.5 +/- 68.6 mug - L-1. h, 74.8 +/- 35.6 mug . L-1. h, and 163.0 +/- 64.6 mug. L-1. h, respectively, with highly significant differences across all 3 study groups (P =.006) and between subjects carrying the *1b and *5 haplotype (P =.002). Strikingly, values of AUC(0-6) from the OATP-C *1b group were more than 60% lower than those derived from carriers of the wild-type OATP-C *1a haplotype, although this difference failed to reach statistical significance. However, the amount of pravastatin excreted into the urine from time 0 to 12 hours [Ae(0-12)] was significantly diminished in the OATP-C *1b haplotype group (1729 t 907 p,g) compared with *1a wild-type control subjects (2974 +/- 1590 mug) (P =.049). Conclusion: There was a significant effect of tested OATP-C variant haplotypes on pravastatin disposition. Whereas *5 expression delayed the hepatocellular uptake of pravastatin, *1b expression seemed to accelerate OATP-C-dependent uptake of the drug.