title: Organic anion transporting polypeptides OATP1B1 and OATP1B3 and their genetic variants influence the pharmacokinetics and pharmacodynamics of raloxifene.
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.
authors.affiliation: Department of Clinical Biochemistry, University of Ljubljana, Ljubljana, Slovenia. barbara.ostanek@ffa.uni-lj.si
authors.forename: Tina
authors.initials: T
authors.lastname: Trdan Lušin
authors.forename: Bruno
authors.initials: B
authors.lastname: Stieger
authors.forename: Janja
authors.initials: J
authors.lastname: Marc
authors.forename: Aleš
authors.initials: A
authors.lastname: Mrhar
authors.forename: Jurij
authors.initials: J
authors.lastname: Trontelj
authors.forename: Andrej
authors.initials: A
authors.lastname: Zavratnik
authors.forename: Barbara
authors.initials: B
authors.lastname: Ostanek
mesh_terms: D015502:Absorptiometry, Photon; D000368:Aged; D000818:Animals; D015519:Bone Density; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D027381:Liver-Specific Organic Anion Transporter 1; D008875:Middle Aged; D027361:Organic Anion Transporters / Q000235:genetics / Q000502:physiology*; D029362:Organic Anion Transporters, Sodium-Independent / Q000235:genetics / Q000502:physiology*; D020849:Raloxifene Hydrochloride / Q000493:pharmacokinetics / Q000494:pharmacology*; D020845:Selective Estrogen Receptor Modulators / Q000493:pharmacokinetics* / Q000494:pharmacology; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3
chemical_list: D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; D029362:Organic Anion Transporters, Sodium-Independent; C503999:SLCO1B1 protein, human; C421209:SLCO1B3 protein, human; D020845:Selective Estrogen Receptor Modulators; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D020849:Raloxifene Hydrochloride