Original ArticleInfluence of hepatic and intestinal efflux transporters and their genetic variants on the pharmacokinetics and pharmacodynamics of raloxifene in osteoporosis treatment
Section snippets
Materials
Raloxifene hydrochloride, fumitremorgin C (Fum C), MK571, verapamil, haloperidol, fluorescein (FLU), dimethylsulfoxide (DMSO), estradiol-17β-glucuronide (E17βG), and formic acid were from Sigma-Aldrich Chemie (Deisenhofen, Germany). Raloxifene metabolites M1, M2, and M3 were synthesized by incubating raloxifene with Streptomyces sp. American Tissue Culture Collection 5504320 followed by semipreparative chromatographic purification and lyophilization. The details of the synthesis and
Passive permeability measurements
The passive part of raloxifene species permeability was assessed with a PAMPA model. The rank order of the compound permeability through the PAMPA membrane shows that raloxifene has the highest passive permeability, followed by raloxifene monoglucuronides and M3, with the lowest passive permeability (Table I).
Transcellular transport assay
Caco-2 cell monolayers were used for the identification of transporters involved in raloxifene transport and for the determination of absorptive raloxifene permeability. The results
Discussion
The main goal of our study was to determine which excretory transporters may play a significant role in the disposition of raloxifene and may also be involved in the observed variability in raloxifene exposure and therapeutic effect. Complex in vitro and in vivo approaches have been used to comprehensively describe the excretory transport of raloxifene and its conjugates. We have shown a strong in vitro evidence of raloxifene species interaction with Pgp and MRP transporters, which encouraged
Conclusions
We discovered which transporters are most likely involved in the excretion of raloxifene species into bile, which is an important step in the enterohepatic recirculation of raloxifene and therefore an important determinant for the overall raloxifene exposure. The presented data implicate that at least a part of the observed variability could be explained by the genetic influence of ABCB1 c.3435C>T polymorphism. In this study, the synergistic use of in vitro models combined with a small in vivo
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Conflict of Interest: none.