Keele Research Repository

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.