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Antimicrobial Agents and Chemotherapy, March 2005, p. 1023-1028, Vol. 49, No. 3
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.3.1023-1028.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Differential Bidirectional Transfer of Indinavir in the Isolated Perfused Human Placenta{dagger}

Sreeja Sudhakaran,1 Hany Ghabrial,2 Roger L. Nation,1 David C. M. Kong,1,3 Neil M. Gude,4 Peter W. Angus,2 and Craig R. Rayner1*

Facility for Anti-Infective Drug Development and Innovation, Monash University,1 Department of Medicine, Austin Health,2 Pharmacy Department, The Alfred Hospital,3 Department of Perinatal Medicine, Royal Women's Hospital, Melbourne, Australia4

Received 23 June 2004/ Returned for modification 29 September 2004/ Accepted 27 October 2004

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 [3H]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; [3H]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.

* Corresponding author. Mailing address: Facility for Anti-Infective Drug Development and Innovation, Monash University, 381 Royal Parade, Parkville, 3052, Melbourne, Australia. Phone: 61-3-9903 9108. Fax: 61-3-9903 9629. E-mail: craig.rayner{at}vcp.monash.edu.au.

{dagger} This research is dedicated to Lori Esch, HIV pharmacotherapy expert, who recently passed away. She was a true inspiration to all who knew her.

Antimicrobial Agents and Chemotherapy, March 2005, p. 1023-1028, Vol. 49, No. 3
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.3.1023-1028.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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