Organic anion transporting polypeptides OATP1B1 and OATP1B3 and their genetic variants influence the pharmacokinetics an
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RESEARCH
Open Access
Organic anion transporting polypeptides OATP1B1 and OATP1B3 and their genetic variants influence the pharmacokinetics and pharmacodynamics of raloxifene Tina Trdan Lušin1, Bruno Stieger2, Janja Marc3, Aleš Mrhar1, Jurij Trontelj1, Andrej Zavratnik4 and Barbara Ostanek3*
Abstract Background: Raloxifene, a selective estrogen receptor modulator, exhibits quite large and unexplained interindividual variability in pharmacokinetics and pharmacodynamics. The aim of this study was to determine the role of organic-anion transporting polypeptides OATP1B1 and OATP1B3 and their genetic variants in the pharmacokinetics and pharmacodynamics of raloxifene. Methods: To test the role of OATP1B1 and OATP1B3 transporters on hepatic uptake of raloxifene and its metabolites an in vitro model of Chinese Hamster Ovary cells expressing OATP1B1 or OATP1B3 was employed. The influence of OATP1B1 and OATP1B3 genetic variants on in vivo pharmacokinetics and pharmacodynamics was evaluated in 53 osteoporotic postmenopausal women treated with raloxifene. Results: Our in vitro results showed that raloxifene and two of the three metabolites, raloxifene-4'-β-glucuronide (M2) and raloxifene-6,4'-diglucuronide (M3), interact with OATP1B1 and OATP1B3. Higher M3 and total raloxifene serum concentrations in patients correlated with lower serum levels of bone resorption marker, serum C-terminal telopeptide fragments of type I collagen, indicating a higher antiresorptive effect of raloxifene. Higher concentrations of M2 correlated with higher increase of lumbar spine bone mineral density supporting the raloxifene vertebral fracture specific protection effect. Finally, raloxifene, M3 and total raloxifene serum concentrations were significantly higher in patients with SLCO1B1 c.388A > G polymorphism and *1b haplotype implicating a considerable genetic effect on pharmacokinetics and pharmacodynamics of raloxifene. Conclusions: These findings indicate that SLCO1B1 c.388A > G polymorphism could play an important role in pharmacokinetics and pharmacodynamics of raloxifene. Keywords: Raloxifene, Raloxifene diglucuronide, SLCO1B1, SLCO1B3, Osteoporosis, LC/MS/MS
Background Raloxifene is a selective estrogen receptor modulator which is approved worldwide for the prevention and treatment of postmenopausal osteoporosis and for the prevention of breast cancer in postmenopausal women. Raloxifene treatment reduces the risk for vertebral fractures [1], increases bone mineral density of lumbar spine (BMD-LS) and of * Correspondence: [email protected] 3 Department of Clinical Biochemistry, Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7 1000, Ljubljana, Slovenia Full list of author information is available at the end of the article
femoral neck (BMD-FN) [2], decreases serum concentrations of bone turnover markers [3,4], stabilizes quantitative ultrasound parameters (QUS) [5,6] and also reduces the risk of invasive breast cancer in postmenopausal women [7]. Beside its beneficial effects on bone and breast tissue, raloxifene dec
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