PT  - JOURNAL ARTICLE
AU  - Collier, Abby C.
AU  - Keelan, Jeffrey A.
AU  - van Zijl, Pierre E.
AU  - Paxton, James W.
AU  - Mitchell, Murray D.
AU  - Tingle, Malcolm D.
TI  - HUMAN PLACENTAL GLUCURONIDATION AND TRANSPORT OF 3′AZIDO-3′-DEOXYTHYMIDINE AND URIDINE DIPHOSPHATE GLUCURONIC ACID
AID  - 10.1124/dmd.32.8.813
DP  - 2004 Aug 01
TA  - Drug Metabolism and Disposition
PG  - 813--820
VI  - 32
IP  - 8
4099  - http://dmd.aspetjournals.org/content/32/8/813.short
4100  - http://dmd.aspetjournals.org/content/32/8/813.full
SO  - Drug Metab Dispos2004 Aug 01; 32
AB  - 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. The American Society for Pharmacology and Experimental Therapeutics