Interactions of tenofovir and tenofovir disoproxil fumarate with drug efflux transporters ABCB1, ABCG2, and ABCC2; role in transport across the placenta

Neumanova, Zuzana; Cerveny, Lukas; Ceckova, Martina; Staud, Frantisek

doi: 10.1097/QAD.0000000000000112
Basic Science

Objective and design: 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.

Conclusion: 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.

Author Information

Department of Pharmacology and Toxicology, Charles University in Prague, Faculty of Pharmacy in Hradec Kralove, Hradec Kralove, Czech Republic.

Correspondence to Professor, PharmDr, Frantisek Staud, Ph.D., Department of Pharmacology and Toxicology, Charles University in Prague, Faculty of Pharmacy in Hradec Kralove, Heyrovskeho 1203, 50005 Hradec Kralove, Czech Republic. Tel: +420 495 067 407; fax: +420 495 067 170; e-mail:

Received 14 August, 2013

Revised 08 October, 2013

Accepted 08 October, 2013

© 2014 Lippincott Williams & Wilkins, Inc.