Placental transfer and fetal metabolism of zidovudine in the baboon.
Zidovudine (azidothymidine, AZT) is used in pregnancy to reduce mother to infant transmission of HIV. Understanding the disposition of AZT in the fetus is necessary to optimize therapeutic regimens directed toward the fetus. Recent studies in primates found similar steady-state levels of the glucuronide metabolite of AZT (AZT-glu) in the fetus to those in the mother, raising the question of whether the metabolite was of fetal or maternal origin. The objective of this study was to determine whether glucuronidation occurred in the fetal compartment and to quantify the placental and fetal clearances of AZT using the two-compartment model at steady state. Steady-state concentrations were obtained after paired maternal and fetal infusions of AZT in chronically catheterized pregnant baboons. During maternal infusion, the mean (+/-SE) fetal to maternal ratio of AZT was < 1 (0.84 +/- 0.06, p < 0.02), suggesting clearance of AZT in the fetus. Mean total maternal clearance of AZT was 725 +/- 49 mL/min and placental clearance was 36 +/- 4 mL/min, or approximately 5% of maternal clearance. Fetal clearance of AZT was estimated at approximately 15% of placental clearance. This suggests fetal nonplacental clearance is minimal compared with that in the mother, but does not preclude the fetus from actively contributing to the metabolite in the fetal circulation. During infusion of AZT to the fetus, the concentration of AZT-glu in the fetus was 7.0 +/- 0.8 times that in the mother. This is compelling evidence that glucuronide can be formed in the fetal compartment. Thus, fetal metabolism has an impact on the concentration of both AZT and AZT-glu in the fetal circulation.
Department of Pediatrics, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA.
M
M
Garland
H H
HH
Szeto
S S
SS
Daniel
P J
PJ
Tropper
M M
MM
Myers
R I
RI
Stark
D000653:Amniotic Fluid / Q000737:chemistry; D000704:Analysis of Variance; D000818:Animals; D005260:Female; D005312:Fetal Blood / Q000378:metabolism; D005333:Fetus / Q000378:metabolism*; D006207:Half-Life; D008431:Maternal-Fetal Exchange; D008657:Metabolic Clearance Rate; D010215:Papio; D010920:Placenta / Q000378:metabolism*; D011247:Pregnancy; D015215:Zidovudine / Q000031:analogs & derivatives / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*
D015215:Zidovudine; C055886:3'-azido-3'-deoxy-5'-O-beta-glucopyranuronosylthymidine