title: Interactions of tenofovir and tenofovir disoproxil fumarate with drug efflux transporters ABCB1, ABCG2, and ABCC2; role in transport across the placenta.
abstract: OBJECTIVE
  Tenofovir (TFV) is used in pregnant women as a part of combination antiretroviral treatment to prevent mother-to-child transmission of HIV infection. We aimed to detect whether TFV and/or its prodrug, tenofovir disoproxil fumarate (TDF), are substrates of ATP-binding cassette (ABC) transporters that are functionally expressed in the placenta, namely P-glycoprotein (ABCB1/MDR1), Breast Cancer Resistance Protein (ABCG2/BCRP) and Multidrug Resistance-Associated Protein 2 (ABCC2/MRP2). We employed in-vitro cell-based assays and in-situ animal model to assess possible role of the efflux transporters in transplacental pharmacokinetics of TFV and TDF.
  
  
  METHODS
  In-vitro transport assays were performed in MDCKII cells transduced with human ABCB1, ABCG2 or ABCC2. To quantify the effect of these transporters on TFV/TDF transplacental passage, we employed the in-situ model of dually perfused rat term placenta in open and closed setup.
  
  
  RESULTS
  In-vitro assays revealed that TDF is a dual substrate of ABCB1 and ABCG2 but not of ABCC2. In contrast, TFV transport was not influenced by any of these transporters. Applying concentration-dependent studies and selective inhibitors, we further confirmed these findings in situ on the organ level; both ABCB1 and ABCG2 limited mother-to-fetus transfer of TDF whereas TFV transplacental passage was not affected by these ABC transporters.
  
  
  CONCLUSIONS
  We propose limited mother-to-fetus transport of both TFV and TDF. While placental transport of TFV is restricted passively, by physical-chemical properties of the molecule, mother-to-fetus passage of TDF is actively hindered by placental ABCB1 and ABCG2 transporters, pumping this compound from trophoblast back to maternal circulation.
authors.affiliation: Department of Pharmacology and Toxicology, Charles University in Prague, Faculty of Pharmacy in Hradec Kralove, Hradec Kralove, Czech Republic.
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Neumanova
authors.forename: Lukas
authors.initials: L
authors.lastname: Cerveny
authors.forename: Martina
authors.initials: M
authors.lastname: Ceckova
authors.forename: Frantisek
authors.initials: F
authors.lastname: Staud
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000225:Adenine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics; D000818:Animals; D019380:Anti-HIV Agents / Q000378:metabolism* / Q000493:pharmacokinetics; D002460:Cell Line; D005260:Female; D006801:Humans; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000378:metabolism*; D063065:Organophosphonates / Q000378:metabolism* / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar; D000068698:Tenofovir
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000225:Adenine; D019380:Anti-HIV Agents; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; D063065:Organophosphonates; D000068698:Tenofovir; C513055:ABCB1 protein, human; C000715087:ABCC2 protein, human; C116614:ABCG2 protein, human