Human placental glucuronidation and transport of 3'azido-3'-deoxythymidine and uridine diphosphate glucuronic acid.
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 microM) 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.
Collier
Abby C
AC
Department of Pharmacology and Clinical Pharmacology, the Liggins Institute, the University of Auckland, Auckland, New Zealand. abbyC@unr.edu
Keelan
Jeffrey A
JA
Van Zijl
Pierre E
PE
Paxton
James W
JW
Mitchell
Murray D
MD
Tingle
Malcolm D
MD
D001692:Biological Transport / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D010920:Placenta / Q000378:metabolism*; D014535:Uridine Diphosphate Glucuronic Acid / Q000378:metabolism*; D015215:Zidovudine / Q000031:analogs & derivatives* / Q000378:metabolism*
D014535:Uridine Diphosphate Glucuronic Acid; D015215:Zidovudine; C055886:3'-azido-3'-deoxy-5'-O-beta-glucopyranuronosylthymidine