Influence of hepatic and intestinal efflux transporters and their genetic variants on the pharmacokinetics and pharmacodynamics of raloxifene in osteoporosis treatment
Trdan Lušin, Tina ...
Raloxifene exhibits a large and unexplained interindividual variability in its pharmacokinetics and pharmacodynamics. The aim of our study was to identify transporters involved in the efflux of ...raloxifene and its glucuronide metabolites by various in vitro models and by an in vivo study to explore the possible involvement of P-glycoprotein (Pgp), multidrug resistance-associated protein (MRP)1, MRP2, MRP3, and breast cancer resistance protein in the observed high interindividual variability. Experiments with the parallel artificial membrane permeability assay showed the highest passive permeability for raloxifene, followed by raloxifene-6-ß-glucuronide (M1), raloxifene-4'-ß-glucuronide (M2), and raloxifene-6,4'-diglucuronide (M3). Caco-2 cell monolayer experiments indicated an interaction of raloxifene with Pgp. The ATPase assay confirmed the raloxifene interaction with Pgp and indicated interactions of all raloxifene species with MRP1, MRP2, MRP3, and breast cancer resistance protein, except for M1, which did not show any interactions with MRP2. Furthermore, the vesicular experiments confirmed the interaction of M2 and M3 with MRP2. Although the in vivo study on osteoporotic postmenopausal women on raloxifene could not confirm a significant influence of ABCB1 and ABCC2 genetic polymorphisms on its pharmacokinetics, a clear trend toward higher total raloxifene concentrations was observed in carriers of at least 1 ABCB1 c.3435T allele. Moreover, the same polymorphism effect was also observed as a significant increase in total hip bone mineral density after 1 year of treatment. The results of our study support the involvement of efflux transporters in disposition of raloxifene and its metabolites and may partially explain the observed raloxifene variability by the influence of the ABCB1 c.3435C>T polymorphism.
It was not necessary to add the material to the shelf.
Bibliographic material was successfully added on shelf.
Adding bibliographical material on shelf was not successful.
Material is already on the shelf.
Permalink
URL:
Impact factor
Access to the JCR database is permitted only to users from Slovenia. Your current IP address is not on the list of IP addresses with access permission, and authentication with the relevant AAI accout is required.
Year
Impact factor
Edition
Category
Classification
JCR
SNIP
JCR
SNIP
JCR
SNIP
JCR
SNIP
Select the library membership card:
DRS,
in which the journal is indexed
Database name
Field
Year
Links to authors' personal bibliographies
Links to information on researchers in the SICRIS system
Subject headings in COBISS General List of Subject Headings
Select pickup location
The material from the parent unit is free. If the material is delivered to the pickup location from another unit, the library may charge you for this service.
PDF
