Etravirine inhibits ABCG2 drug transporter and affects transplacental passage of tenofovir disoproxil fumarate
Abstrakt
All HIV positive pregnant women should receive combination antiretroviral therapy (cART) to prevent mother-to-child transmission (MTCT) of the virus. It has recently been shown that fetal exposure of nucleoside reverse transcriptase inhibitors (NRTIs) tenofovir disoproxil fumarate (TDF) and abacavir is decreased by placental ABC transporters p-glycoprotein (ABCB1) and BCRP (ABCG2).
The aim of this study was to evaluate transporter-mediated drug-drug interactions (DDI) between etravirine (TMC125), a novel non-nucleoside reverse transcriptase inhibitor used in cART, and the NRTIs and to assess the relevance of such DDI for transplacental pharmacokinetics of TDF and abacavir. We confirmed significant inhibition of ABCG2 but not ABCB1 by etravirine in hoechst accumulation assays.
In transport studies on MDCKII-ABCG2 monolayers etravirine completely abolished the ABCG2-mediated transfer of [3H]-TDF. Similar effect was observed in [3H]-abacavir albeit at markedly lower etravirine concentration.
Using dually perfused rat placenta, etravirine co-administration resulted in reduced fetal-to-maternal passage of TDF but not abacavir.