No abstract

The study revealed substantial induction of several drug transporters by saquinavir and darunavir, possibly leading to decreased efficacy of antiretrovirals and drugs used to treat co-morbidity.

The new antiretrovirals bear the potential to modulate expression and function of several ABC transporters, with elvitegravir revealing the highest interaction potential.

Etravirine is a novel nonnucleoside reverse transcriptase inhibitor (NNRTI) for the treatment of HIV-1 infections. ABC transporters potentially mediate clinically relevant drug-drug interactions. We assessed substrate characteristics and the inhibitory and inductive potential of etravirine on ABC transporters. Etravirine did not inhibit P-gp/ABCB1 and was not transported by the tested ABC transporters but was a potent inhibitor of BCRP/ABCG2. Etravirine induced several ABC transporters, especially BCRP/ABCG2. These data demonstrate that etravirine has the potential for drug-drug interactions by modulation of expression and function of several ABC transporters.Etravirine is a novel nonnucleoside reverse transcriptase inhibitor (NNRTI) for the treatment of HIV-1 infections. It is active against wild-type and some NNRTI-resistant HIV strains (1, 2) and offers a new treatment option for treatmentexperienced patients. Pharmacokinetic drug-drug interactions considerably influence efficacy and safety of antiretroviral therapy. Interactions might lower concentrations of antiretrovirals below therapeutic concentrations (5,12,14) and cause treatment failure and viral resistance. Interactions may also increase drug exposure and augment toxicity.The main mechanisms of interaction in antiretroviral combination therapy involve the drug-metabolizing cytochrome P450 enzymes (CYPs) as well as efflux and uptake transporters. Crucial efflux transporters are several ATP-binding cassette (ABC) transporters that have been identified as important interaction sites of antiretroviral drugs (9-11). Relevant uptake transporters are the organic anion-transporting polypeptides (OATPs/SLCOs) (6,16,20). Information on interactions of etravirine is sparse. We therefore investigated whether etravirine is a substrate of P-gp/ABCB1, BCRP/ABCG2, MRP1/ ABCC1, MRP2/ABCC2, or MRP3/ABCC3 and whether it inhibits P-gp/ABCB1 and BCRP/ABCG2. Furthermore, we investigated etravirine's potency to induce ABC transporters, important OATPs/SLCOs, CYPs, and the transcription factor pregnane X receptor.Etravirine was obtained through the NIH AIDS Research and Reference Reagent Program, Division of AIDS, NIAID, NIH, as etravirine TMC125 (catalog no. 11609) from Tibotec, Inc. Other materials were used as described previously (13). Etravirine was tested for cytotoxic effects prior to P-gp/ABCB1 and BCRP/ABCG2 inhibition assays with a cytotoxicity detection kit (Roche Applied Science, Mannheim, Germany) according to manufacturer's instructions. Cytotoxic concentrations were excluded in the respective assays. P-gp/ABCB1 and BCRP/ABCG2 inhibition was quantified by calcein and pheophorbide A efflux assays as described previously (23, 26). We used the growth inhibition assay in MDCKII cells overexpressing human P-gp/ABCB1 (7), BCRP/ABCG2 (17), and MRP1-3/ABCC1-3 (8) as a surrogate for substrate characteristics of etravirine as it has been described for other antiretroviral drugs (3,13,26). The induction assay, quantification of mRNA expression by real-time reverse transc...