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Raltegravir is a substrate for SLC22A6: A putative mechanism for the interaction between raltegravir and tenofovir

Raltegravir is a substrate for SLC22A6: A putative mechanism for the interaction between raltegravir and tenofovir Thumbnail


Abstract

The identification of transporters of the HIV integrase inhibitor raltegravir could be a factor in an understanding of the pharmacokinetic-pharmacodynamic relationship and reported drug interactions of raltegravir.
Here we determined whether raltegravir was a substrate for ABCB1 or the influx transporters SLCO1A2,
SLCO1B1, SLCO1B3, SLC22A1, SLC22A6, SLC10A1, SLC15A1, and SLC15A2. Raltegravir transport by
ABCB1 was studied with CEM, CEMVBL100, and Caco-2 cells. Transport by uptake transporters was assessed
by using a Xenopus laevis oocyte expression system, peripheral blood mononuclear cells, and primary renal
cells. The kinetics of raltegravir transport and competition between raltegravir and tenofovir were also
investigated using SLC22A6-expressing oocytes. Raltegravir was confirmed to be an ABCB1 substrate in CEM,
CEMVBL100, and Caco-2 cells. Raltegravir was also transported by SLC22A6 and SLC15A1 in oocyte expression
systems but not by other transporters studied. The Km and Vmax for SLC22A6 transport were 150 ?M and 36
pmol/oocyte/h, respectively. Tenofovir and raltegravir competed for SLC22A6 transport in a concentrationdependent manner. Raltegravir inhibited 1 ?M tenofovir with a 50% inhibitory concentration (IC50) of 14.0
?M, and tenofovir inhibited 1 ?M raltegravir with an IC50 of 27.3 ?M. Raltegravir concentrations were not
altered by transporter inhibitors in peripheral blood mononuclear cells or primary renal cells. Raltegravir is
a substrate for SLC22A6 and SLC15A1 in the oocyte expression system. However, transport was limited
compared to endogenous controls, and these transporters are unlikely to have a great impact on raltegravir
pharmacokinetics.

Acceptance Date Nov 2, 2010
Publication Date Feb 1, 2011
Journal Antimicrobial Agents and Chemotherapy
Print ISSN 0066-4804
Publisher American Society for Microbiology
Pages 879-887
DOI https://doi.org/10.1128/AAC.00623-10
Publisher URL http://aac.asm.org/content/55/2/879

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