Effects of grapefruit juice and SLCO1B1 388A>G polymorphism on the pharmacokinetics of pitavastatin

Pitavastatin undergoes little hepatic metabolism but it is a substrate for uptake and efflux transporters, particularly OATP1B1 (gene SLCO1B1). A previous study in 8 Japanese healthy subjects showed that co-administration with grapefruit juice (GFJ) resulted in a small increase in systemic exposure to pitavastatin. We examined whether common polymorphisms in SLCO1B1 might influence the pharmacokinetics of pitavastatin or the interaction with GFJ. Twelve Chinese healthy male volunteers took pitavastatin 2 mg orally with water or with GFJ on separate occasions and plasma concentrations of pitavastatin acid and lactone were measured over 48 h. GFJ increased the mean area under the plasma concentration-time curve (AUC0-48 h) for both pitavastatin acid and lactone by 14% (p<0.05). Subjects with SLCO1B1 *1b/*1b haplotype (388GG-521TT) had 47% and 44% higher systemic exposure for pitavastatin acid and lactone than the SLCO1B1 *1a carriers (388AA/AG-521TT, p<0.05 and p=0.005, respectively). The SLCO1B1 388A>G polymorphism, which increases transporter activity for some statins, was associated with higher plasma levels of pitavastatin acid and lactone in subjects with the homozygous variant indicating decreased hepatic uptake. Co-administration of pitavastatin with GFJ resulted in a small but significant increase in plasma levels in healthy Chinese subjects.