title: Etravirine inhibits ABCG2 drug transporter and affects transplacental passage of tenofovir disoproxil fumarate.
abstract: 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.
authors: Charles University in Prague, Faculty of Pharmacy in Hradec Kralove, Department of Pharmacology and Toxicology, Heyrovskeho 1203, Hradec Kralove, Czech Republic.
authors: Josef
authors: J
authors: Reznicek
authors: Charles University in Prague, Faculty of Pharmacy in Hradec Kralove, Department of Pharmacology and Toxicology, Heyrovskeho 1203, Hradec Kralove, Czech Republic.
authors: Martina
authors: M
authors: Ceckova
authors: Charles University in Prague, Faculty of Pharmacy in Hradec Kralove, Department of Pharmacology and Toxicology, Heyrovskeho 1203, Hradec Kralove, Czech Republic.
authors: Lenka
authors: L
authors: Tupova
authors: Charles University in Prague, Faculty of Pharmacy in Hradec Kralove, Department of Pharmacology and Toxicology, Heyrovskeho 1203, Hradec Kralove, Czech Republic. Electronic address: frantisek.staud@faf.cuni.cz.
authors: Frantisek
authors: F
authors: Staud
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2 / Q000378:metabolism*; D000818:Animals; D019380:Anti-HIV Agents / Q000494:pharmacology*; D002460:Cell Line; D005260:Female; D006801:Humans; D009570:Nitriles; D010920:Placenta / Q000187:drug effects* / Q000378:metabolism; D011247:Pregnancy; D011724:Pyridazines / Q000494:pharmacology*; D011743:Pyrimidines; D051381:Rats; D017208:Rats, Wistar; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*; D000068698:Tenofovir / Q000494:pharmacology*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D019380:Anti-HIV Agents; D009570:Nitriles; D011724:Pyridazines; D011743:Pyrimidines; D018894:Reverse Transcriptase Inhibitors; C451734:etravirine; D000068698:Tenofovir
keywords: Abacavir; Breast cancer resistance protein; P-glycoprotein; Pregnancy; Tenofovir disoproxil fumarate; Transplacental pharmacokinetics