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 i n the fetus is necessary to optimize therapeutic regimens directed tow ard the fetus. Recent studies in primates found similar steady-state l evels of the glucuronide metabolite of AZT (AZT-glu) in the fetus to t hose in the mother, raising the question of whether the metabolite was of fetal or maternal origin. The objective of this study was to deter mine whether glucuronidation occurred in the fetal compartment and to quantify the placental and fetal clearances of AZT using the two-compa rtment model at steady state. Steady-state concentrations were obtaine d after paired maternal and fetal infusions of AZT in chronically cath eterized pregnant baboons. During maternal infusion, the mean (+/-SE) fetal to maternal ratio of AZT was <1 (0.84 +/- 0.06, p < 0.02), sugge sting 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 similar to 5% of maternal clearance. Fetal clearance of AZT was es timated at similar to 15% of placental clearance. This suggests fetal nonplacental clearance is minimal compared with that in the mother, bu t does not preclude the fetus from actively contributing to the metabo lite in the fetal circulation. During infusion of AZT to the fetus, th e 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.