Inhibition of placental P-glycoprotein: impact on indinavir transfer to the foetus

AIMS To investigate the effect of P-gp inhibition on the maternal to foetal transfer of indinavir. METHODS Term human placentae (n = 12) were from non-HIV infected women. Maternal to foetal transfer of indinavir was examined in the absence and presence of P-gp inhibitors PSC833 (n = 7) or ritonavir (n = 5), in the perfused human placenta. Antipyrine and [H-3]-vinblastine were included as markers of passive diffusion and P-gp transport, respectively. These markers and indinavir were added to maternal perfusate at 0 min; PSC833 or ritonavir was added at 25 min. Steady-state maternal to foetal transfer clearance was calculated during control and inhibitor phases. Indinavir and vinblastine clearances were normalized to antipyrine clearance (clearance index). RESULTS Indinavir clearance index increased between the control (0.25 +/- 0.03) and PSC833 phases (0.37 +/- 0.14) (95% CI of the difference -0.23, -0.002). Vinblastine clearance index increased from (0.25 +/- 0.08) to (0.34 +/- 0.06) in the control and PSC833 phases, respectively (95% CI of difference -0.14, -0.05). Indinavir clearance index was unchanged between control (0.34 +/- 0.14) and ritonavir phases (0.39 +/- 0.13) (95% CI of the difference -0.19, 0.08). Vinblastine clearance index increased from (0.24 +/- 0.12) to (0.32 +/- 0.12) in the control and ritonavir phases, respectively (95% CI of the difference -0.15, -0.009). CONCLUSIONS Maternal to foetal transfer clearance of indinavir and vinblastine increased following P-gp inhibition. The potential role for co-administration of P-gp inhibitors with PIs to reduce perinatal HIV transmission warrants further investigation.