Organic anion transporting polypeptides OATP1B1 and OATP1B3 and their genetic variants influence the pharmacokinetics and pharmacodynamics of raloxifene (Journal of Translational Medicine)

Background: Raloxifene, a selective estrogen receptor modulator, exhibits quite large and unexplainedinterindividual variability in pharmacokinetics and pharmacodynamics. The aim of this studywas to determine the role of organic-anion transporting polypeptides OATP1B1 andOATP1B3 and their genetic variants in the pharmacokinetics and pharmacodynamics ofraloxifene. Methods: To test the role of OATP1B1 and OATP1B3 transporters on hepatic uptake of raloxifene andits metabolites an in vitro model of Chinese Hamster Ovary cells expressing OATP1B1 orOATP1B3 was employed. The influence of OATP1B1 and OATP1B3 genetic variants on invivo pharmacokinetics and pharmacodynamics was evaluated in 53 osteoporoticpostmenopausal women treated with raloxifene. Results: Our in vitro results showed that raloxifene and two of the three metabolites, raloxifene-4`-beta-glucuronide (M2) and raloxifene-6,4`-diglucuronide (M3), interact with OATP1B1 andOATP1B3. Higher M3 and total raloxifene serum concentrations in patients correlated withlower serum levels of bone resorption marker, serum C-terminal telopeptide fragments oftype I collagen, indicating a higher antiresorptive effect of raloxifene. Higher concentrationsof M2 correlated with higher increase of lumbar spine bone mineral density supporting theraloxifene vertebral fracture specific protection effect. Finally, raloxifene, M3 and totalraloxifene serum concentrations were significantly higher in patients with SLCO1B1c.388A > G polymorphism and *1b haplotype implicating a considerable genetic effect onpharmacokinetics and pharmacodynamics of raloxifene. Conclusions: These findings indicate that SLCO1B1 c.388A > G polymorphism could play an importantrole in pharmacokinetics and pharmacodynamics of raloxifene.