Placental transfer of maraviroc in an ex vivo human cotyledon perfusion model and influence of ABC transporter expression

Antimicrob Agents Chemother. 2013 Mar;57(3):1415-20. doi: 10.1128/AAC.01821-12. Epub 2013 Jan 7.

Abstract

Nowadays, antiretroviral therapy is recommended during pregnancy to prevent mother-to-child transmission of HIV. However, for many antiretroviral drugs, including maraviroc, a CCR5 antagonist, very little data exist regarding placental transfer. Besides, various factors may modulate this transfer, including efflux transporters belonging to the ATP-binding cassette (ABC) transporter superfamily. We investigated maraviroc placental transfer and the influence of ABC transporter expression on this transfer using the human cotyledon perfusion model. Term placentas were perfused ex vivo for 90 min with maraviroc (600 ng/ml) either in the maternal-to-fetal (n = 10 placentas) or fetal-to-maternal (n = 6 placentas) direction. Plasma concentrations were determined by ultra performance liquid chromatography coupled with tandem mass spectrometry (UPLC-MS/MS). Fetal transfer rates (FTR) and clearance indexes (CLI) were calculated as ratios of fetal to maternal concentrations at steady state (mean values between 30 and 90 min) and ratios of FTR of maraviroc to that of antipyrine, respectively. ABC transporter gene expression levels were determined by quantitative reverse transcription (RT)-PCR and ABCB1 protein expression by Western blotting. For the maternal-to-fetal direction, the mean FTR and CLI were 8.0% ± 3.0 and 0.26 ± 0.07, respectively, whereas the mean CLI was 0.52 ± 0.23 for the fetal-to-maternal direction. We showed a significant inverse correlation between maraviroc CLI and ABCC2, ABCC10, and ABCC11 placental gene expression levels (P < 0.05). To conclude, we report a low maraviroc placental transfer probably involving ABC efflux transporters and thus in all likelihood associated with a limited fetal exposition. Nevertheless, these results would need to be supported by in vivo data obtained from paired maternal and cord blood samples.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
  • ATP-Binding Cassette Transporters / genetics
  • ATP-Binding Cassette Transporters / metabolism
  • Chromatography, Liquid
  • Cyclohexanes / metabolism*
  • Cyclohexanes / pharmacology
  • Diffusion Chambers, Culture
  • Female
  • Fetus
  • Gene Expression*
  • HIV Fusion Inhibitors / metabolism*
  • HIV Fusion Inhibitors / pharmacology
  • Humans
  • Kinetics
  • Maraviroc
  • Maternal-Fetal Exchange
  • Models, Biological*
  • Multidrug Resistance-Associated Proteins / genetics
  • Multidrug Resistance-Associated Proteins / metabolism
  • Organ Culture Techniques
  • Perfusion
  • Placenta / drug effects
  • Placenta / metabolism*
  • Pregnancy
  • Tandem Mass Spectrometry
  • Triazoles / metabolism*
  • Triazoles / pharmacology

Substances

  • ABCB1 protein, human
  • ABCC10 protein, human
  • ABCC11 protein, human
  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • ATP-Binding Cassette Transporters
  • Cyclohexanes
  • HIV Fusion Inhibitors
  • Multidrug Resistance-Associated Proteins
  • Triazoles
  • multidrug resistance-associated protein 2
  • Maraviroc