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0090-9556/04/3208-813-820$20.00
DMD 32:813-820, 2004

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HUMAN PLACENTAL GLUCURONIDATION AND TRANSPORT OF 3'AZIDO-3'-DEOXYTHYMIDINE AND URIDINE DIPHOSPHATE GLUCURONIC ACID

Abby C. Collier, Jeffrey A. Keelan, Pierre E. van Zijl, James W. Paxton, Murray D. Mitchell, and Malcolm D. Tingle

Department of Pharmacology and Clinical Pharmacology (A.C.C., J.A.K., J.W.P., M.D.T.), the Liggins Institute (A.C.C., J.A.K., P.E.v.Z., M.D.M.), and Department of Obstetrics and Gynecology (M.D.M.), the University of Auckland, Auckland, New Zealand

These studies were performed to characterize the contribution of the uridine diphosphate glucuronosyltransferase (UGT) enzymes to the clearance of 3'-azido-3'-deoxythymidine (AZT) in vivo and to assess the regulation of UGT activity [including the disposition of the cofactor uridine diphosphate glucuronic acid (UDPGA)] in the placenta. Transport of AZT and the cofactor UDPGA across the human placenta and the glucuronidation capacity of the placenta for AZT were assessed using a human placental cell line (JEG-3), primary cultures of villous term placenta, placental subcellular fractions, and a recirculating perfusion model. Glucuronidation of AZT was consistently observed at approximately 2% of the dose administered. High levels of AZT in cultured primary placental cells and lines caused autoinhibition of AZT metabolism. AZT crossed the perfused placenta in a bidirectional fashion and was at equilibrium after 3 h, whereas the AZT-glucuronide metabolite was excreted preferentially into the maternal compartment. In contrast, UDPGA (10 µM) was rapidly transferred from the maternal to the fetal circulation, being complete after 4 h of perfusion. AZT is transported and glucuronidated by the human placenta, but that placental metabolism of the drug is not significant for whole-body clearance. Likewise therapeutic failure of AZT (5–15%) is not due to placental obstruction of drug passage. Finally, the activity of the UGT enzymes in the placenta is not rate-limited by the supply of UDPGA cofactor, whereas the preferential transport of UDPGA toward the fetus observed here may indicate a role in fetal development.

Address correspondence to: Abby Collier, University of Nevada, Reno, MS 199, Reno, NV 89557. E-mail: abbyC{at}unr.edu




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