title: Differential bidirectional transfer of indinavir in the isolated perfused human placenta.
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.
authors.affiliation: Facility for Anti-Infective Drug Development and Innovation, Monash University, 381 Royal Parade, Parkville, 3052, Melbourne, Australia.
authors.forename: Sreeja
authors.initials: S
authors.lastname: Sudhakaran
authors.forename: Hany
authors.initials: H
authors.lastname: Ghabrial
authors.forename: Roger L
authors.initials: RL
authors.lastname: Nation
authors.forename: David C M
authors.initials: DC
authors.lastname: Kong
authors.forename: Neil M
authors.initials: NM
authors.lastname: Gude
authors.forename: Peter W
authors.initials: PW
authors.lastname: Angus
authors.forename: Craig R
authors.initials: CR
authors.lastname: Rayner
mesh_terms: D001692:Biological Transport; D005260:Female; D015658:HIV Infections / Q000188:drug therapy; D017320:HIV Protease Inhibitors / Q000493:pharmacokinetics*; D006801:Humans; D019469:Indinavir / Q000493:pharmacokinetics*; D008431:Maternal-Fetal Exchange; D010477:Perfusion; D010920:Placenta / Q000378:metabolism*; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious / Q000188:drug therapy
chemical_list: D017320:HIV Protease Inhibitors; D019469:Indinavir
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