Differential Bidirectional Transfer of Indinavir in the Isolated Perfused Human Placenta

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Abstract
The protease inhibitor (PI) indinavir may be used in the management of human immunodeficiency virus (HIV) infection during pregnancy. Poor maternal-to-fetal transfer of indinavir has been reported previously, but the mechanisms of transfer remain unknown. The bidirectional transfer of indinavir was assessed in dually perfused, isolated human placentae. Term placentae ( n = 5) were obtained from non-HIV-infected pregnant women. To investigate transport mechanisms, the steady-state transfer of indinavir was compared to those of antipyrine (a marker of passive diffusion) and [ 3 H]vinblastine (a marker of P-glycoprotein [P-gp] transport) in the maternal-to-fetal and fetal-to-maternal directions in each placenta. Indinavir and antipyrine perfusate concentrations were determined by using reverse-phase, high-performance liquid chromatography; [ 3 H]vinblastine concentrations were measured by liquid scintillation. The antipyrine transfer clearance in each direction did not differ ( P = 0.76), a finding consistent with passive diffusion. However, the maternal-to-fetal transfer clearance of vinblastine, normalized to that of antipyrine (clearance index) (0.31 ± 0.05), was significantly lower than the fetal-to-maternal clearance index of vinblastine (0.67 ± 0.17; P = 0.017), suggesting the involvement of placental P-gp. Similarly, the maternal-to-fetal clearance index of indinavir (0.39 ± 0.09) was significantly lower than its fetal-to-maternal clearance index (0.97 ± 0.12; P < 0.001). These results represent the first evidence for differential transfer of a xenobiotic in the intact human placenta. The use of transport modulators to increase the maternal-to-fetal transfer of PIs as a possible strategy to reduce mother-to-child transmission of HIV warrants investigation.