Effect of OATP1B1 (SLCO1B1) variant alleles on the pharmacokinetics of pitavastatin in healthy volunteers

Background: Pitavastatin is a potent, newly developed 3-hydroxy-3-methylglutaryl–coenzyme A reductase inhibitor for the treatment of hyperlipidemia. We characterized the effects of organic anion transporting polypeptide 1B1 (OATP1B1) alleles *1a, *1b, and *15 on the pharmacokinetics of pitavastatin. Methods: Twenty-four healthy Korean volunteers who had previously participated in a pharmacokinetic study of pitavastatin (single oral dose, 1-8 mg) were further investigated. Subjects were grouped according to OATP1B1 genotype. Dose-normalized area under the plasma concentration–time curve (AUC) and peak plasma concentration (C_max) values were analyzed, because different dosages were administered to subjects, whereas the pharmacokinetics showed linear characteristics. Results: Dose-normalized pitavastatin AUCs for *1b/*1b (group 1), *1a/*1a or *1a/*1b (group 2), and *1a/*15 or *1b/*15 (group 3) were 38.8 ± 13.3, 54.4 ± 12.4, and 68.1 ± 16.3 ng·h·mL⁻¹ ·mg⁻¹ (mean ± SD), respectively, with significant differences between all 3 groups (P = .008) and between subjects carrying and those not carrying the *15 allele (P = .004). Dose-normalized pitavastatin C_max values were 13.2 ± 3.3, 18.2 ± 5.7, and 29.4 ± 9.6 ng·mL⁻¹ ·mg⁻¹ in groups 1, 2, and 3, respectively, and also showed significant differences (P = .003) in a manner similar to that shown by AUC. No significant differences were found between the genotype groups in terms of dose-normalized AUC or C_max values of pitavastatin lactone. Conclusion: OATP1B1 variant haplotypes were found to have a significant effect on the pharmacokinetics of pitavastatin. These results suggest that the *15 allele is associated with decreased pitavastatin uptake from blood into hepatocytes and that OATP1B1 genetic polymorphisms have no effect on the pharmacokinetics of pitavastatin lactone. [Copyright &y& Elsevier]