Effects of the SLCO1B1*15 allele on the pharmacokinetics of pitavastatin

1. The hepatic uptake of pitavastatin is mediated by carriers, especially OATP1B1, which is encoded by the SLCO1B1 gene. Because the liver is a target organ of pitavastatin, OATP1B1 is responsible for both the pharmacological effects and clearance of pitavastatin. The effects of the SLCO1B1*15 allele on the pharmacokinetics (PK) of pitavastatin were studied. 2. Pitavastatin 2mg was orally administered to 38 subjects with SLCO1B1*1a/*1b (n=20), *1b/*15 (n=13), or *15/*15 (n=5). After pitavastatin administration, the plasma concentrations of pitavastatin and pitavastatin lactone were assayed for up to 48h using liquid chromatography-tandem mass spectrometry. 3. In comparison to the SLCO1B1*1a/*1b subjects, only a C _max was slightly higher in the SLCO1B1*1b/*15 subjects. However, the SLCO1B1*15/*15 subjects had a 1.74-fold higher AUC _inf (285.5±14.5 vs. 164.6±41.3 ng·h/mL; p<0.001), a 2.21-fold higher C _max (106.7±15.1 vs. 48.3±13.4ng/mL; p<0.001), and a 47.3% lower apparent oral clearance (13.1±3.9 vs. 6.9±0.4L/h; p<0.001) of pitavastatin. 4. For pitavastatin lactone, there were no significant differences in AUC _inf, C _max, t _1/2, and t _max among the three genotypes. 5. Unlike previous studies, the disposition of pitavastatin exposure was not altered in subjects with the SLCO1B1*1b/*15 genotype, except C _max. However, pitavastatin exposure was significantly increased in subjects with the SLCO1B1*15/*15 genotype due to reduced hepatic absorption.