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Division of Neurotoxicology, HFT-132, National Center for
Toxicological Research/Food and Drug Administration
3
-Azido-3-deoxythymidine (AZT) is currently prescribed to
pregnant women infected with human immunodeficiency virus to reduce the
risk of vertical transmission of the virus to the fetus. Consequently, more information is needed concerning the placental transfer and tissue
distribution of AZT and its metabolites. In the present study, the
placental transfer and fetal accumulation of AZT, its glucuronide
metabolite [3-azido-3-deoxythymidine-
-D-glucuronide (AZTG)], and phosphorylated metabolites were examined at steady-state in near-term rhesus macaques. One to 2 weeks before a chronic infusion,
an intravenous bolus of 8 mg/kg AZT was administered to pregnant
animals to determine the dose of AZT needed to reach steady-state
plasma concentrations. On the day of hysterotomy, the mother was
administered an intravenous loading dose of AZT, followed by a 3-hr
steady-state intravenous infusion that also included a trace of
[3H]AZT. After 3 hr of infusion, the mother was
anesthetized, and the fetus was delivered. Plasma and amniotic fluid
were analyzed for AZT and AZTG by HPLC, and tissue samples were
analyzed for AZT, AZTG, and phosphorylated metabolites by strong anion
exchange HPLC. Maternal steady-state plasma concentrations were
1.3-2.2 µg/ml for AZT and 2.3-8.0 µg/ml for AZTG. Fetal AZT and
AZTG plasma concentrations were both lower (0.98-2.3 µg/ml and
1.3-5.4 µg/ml, respectively) than maternal concentrations, with
fetal-to-maternal plasma ratios of 0.63-1.0 for AZT. Fetal tissue
distribution of tritium was highest in the kidney and lowest in the
brain. Although the active triphosphorylated metabolite was not
detected in the fetus, the AZT-monophosphate was detected in almost all
fetal tissues examined. Our data indicate that AZT is rapidly converted to the glucuronide and monophosphate metabolites in the fetus after
maternal infusion.
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