Etravirine inhibits ABCG2 drug transporter and affects transplacental passage of tenofovir disoproxil fumarate
Abstract Introduction 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 fumar...
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Published in | Placenta (Eastbourne) Vol. 47; pp. 124 - 129 |
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Language | English |
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01.11.2016
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Abstract | Abstract Introduction 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. Methods In vitro accumulation assays and transport experiments on ABCB1 and ABCG2 overexpressing MDCKII monolayers were employed. Furthermore, the effect of etravirine on the transplacental passage of TDF and abacavir was assessed using in situ dually perfused rat placenta. Results 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 [3 H]-TDF. Similar effect was observed in [3 H]-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. Discussion Etravirine is able to affect transplacental passage of TDF but not that of abacavir through interactions on ABCG2. These results should be considered when introducing etravirine into TDF-containing cART in pregnancy. |
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AbstractList | 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.
In vitro accumulation assays and transport experiments on ABCB1 and ABCG2 overexpressing MDCKII monolayers were employed. Furthermore, the effect of etravirine on the transplacental passage of TDF and abacavir was assessed using in situ dually perfused rat placenta.
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.
Etravirine is able to affect transplacental passage of TDF but not that of abacavir through interactions on ABCG2. These results should be considered when introducing etravirine into TDF-containing cART in pregnancy.
•Etravirine is an inhibitor of ABCG2 but not ABCB1 in vitro able to inhibit ABCG2-mediated efflux of TDF and abacavir.•Through inhibition of ABCG2, etravirine increases placental passage of tenofovir disoproxil fumarate from mother to fetus.•ABCG2-mediated pharmacokinetic DDI of etravirine with ABCG2 substrates during pharmacotherapy of HIV infection may occur. Abstract Introduction 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. Methods In vitro accumulation assays and transport experiments on ABCB1 and ABCG2 overexpressing MDCKII monolayers were employed. Furthermore, the effect of etravirine on the transplacental passage of TDF and abacavir was assessed using in situ dually perfused rat placenta. Results 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 [3 H]-TDF. Similar effect was observed in [3 H]-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. Discussion Etravirine is able to affect transplacental passage of TDF but not that of abacavir through interactions on ABCG2. These results should be considered when introducing etravirine into TDF-containing cART in pregnancy. 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. In vitro accumulation assays and transport experiments on ABCB1 and ABCG2 overexpressing MDCKII monolayers were employed. Furthermore, the effect of etravirine on the transplacental passage of TDF and abacavir was assessed using in situ dually perfused rat placenta. 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 [ H]-TDF. Similar effect was observed in [ H]-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. Etravirine is able to affect transplacental passage of TDF but not that of abacavir through interactions on ABCG2. These results should be considered when introducing etravirine into TDF-containing cART in pregnancy. |
Author | Josef, Reznicek Martina, Ceckova Lenka, Tupova Frantisek, Staud |
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Keywords | P-glycoprotein Pregnancy Breast cancer resistance protein Tenofovir disoproxil fumarate Abacavir Transplacental pharmacokinetics |
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Snippet | Abstract Introduction All HIV positive pregnant women should receive combination antiretroviral therapy (cART) to prevent mother-to-child transmission (MTCT)... All HIV positive pregnant women should receive combination antiretroviral therapy (cART) to prevent mother-to-child transmission (MTCT) of the virus. It has... |
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SubjectTerms | Abacavir Animals Anti-HIV Agents - pharmacology ATP Binding Cassette Transporter, Sub-Family G, Member 2 - metabolism ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism Breast cancer resistance protein Cell Line Female Humans Internal Medicine Obstetrics and Gynecology P-glycoprotein Placenta - drug effects Placenta - metabolism Pregnancy Pyridazines - pharmacology Rats Rats, Wistar Reverse Transcriptase Inhibitors - pharmacology Tenofovir - pharmacology Tenofovir disoproxil fumarate Transplacental pharmacokinetics |
Title | Etravirine inhibits ABCG2 drug transporter and affects transplacental passage of tenofovir disoproxil fumarate |
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