RT Journal Article
SR Electronic
T1 INTERACTIONS BETWEEN MARAVIROC AND THE ABCB1, ABCG2 AND ABCC2 TRANSPORTERS: AN IMPORTANT ROLE IN TRANSPLACENTAL PHARMACOKINETICS
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP dmd.119.087684
DO 10.1124/dmd.119.087684
A1 Lenka Tupova
A1 Martina Ceckova
A1 Csilla Ambrus
A1 Ales Sorf
A1 Zuzana Ptackova
A1 Zsuzsanna Gaborik
A1 Frantisek Staud
YR 2019
UL http://dmd.aspetjournals.org/content/early/2019/07/02/dmd.119.087684.abstract
AB Maraviroc is a chemokine receptor 5 (CCR5) inhibitor used in the treatment of HIV that also shows therapeutic potential for several autoimmune, cancer and inflammatory diseases that can afflict pregnant women. However, only limited information exists on the mechanisms underlying the transplacental transfer of the drug. We aimed to expand the current knowledge base on how maraviroc interacts with several placental ABC efflux transporters that have a recognized role in the protection of a developing fetus, i.e. ABCB1, ABCG2 and ABCC2. We found that maraviroc does not inhibit any of the three studied ABC transporters, and that its permeability is not affected by ABCG2 or ABCC2. However, our in vitro results revealed that maraviroc shows affinity for human ABCB1 and the endogenous canine Abcb1 expressed in MDCKII cells. Perfusion of rat term placenta showed accelerated transport of maraviroc in the feto-maternal direction, which suggests that ABCB1/Abcb1 facilitate in situ maraviroc transport. This transplacental transport was saturable and significantly diminished following the addition of the ABCB1/Abcb1 inhibitors elacridar, zosuquidar, and ritonavir. Our results indicate that neither ABCG2 nor ABCC2 influence maraviroc pharmacokinetic, but that ABCB1/Abcb1 may be partly responsible for the decreased transplacental permeability of maraviroc to the fetus. The strong affinity of maraviroc to Abcb1 found in our animal models necessitates studies in human tissue so that maraviroc pharmacokinetics in pregnant women can be fully understood.SIGNIFICANCE STATEMENT Antiretroviral drug maraviroc shows low toxicity potential and therefore it is a good candidate for prevention of mother-to-child transmission of HIV when failure of recommended therapy occurs. Although previous studies suggested interactions of maraviroc with ABCB1 transporter and its limited transfer across the placenta, this interaction has never been tested functionally in placental tissue. Using in vitro cell-based experiments and in situ method of dually perfused rat term placenta, here we examined maraviroc interactions with the three most important placental ABC drug transporters, ABCB1, ABCG2 and ABCC2. We demonstrate for the first time that placental ABCB1 significantly decreases mother-to-fetus transport of maraviroc. We conclude that ABCB1 may be responsible for the low cord blood/maternal blood ratio observed in humans.