Abstract
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-β-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.
Footnotes
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Send reprint requests to: Dr. Tucker A. Patterson, Division of Neurotoxicology, HFT-132, National Center for Toxicological Research/Food and Drug Administration, 3900 NCTR Road, Jefferson, AR 72079-9502.
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T. A. Patterson and J. A. Sandberg were supported in part by appointment to the Postgraduate Research Program in the Division of Neurotoxicology at the NCTR administered by Oak Ridge Institute for Science Education through an interagency agreement between the U.S. Department of Energy and the U.S. Food and Drug Administration. This work was supported in part by an interagency agreement between the NCTR and the National Institute for Environmental Health Sciences (IAG Y01-ES-10187).
- Abbreviations used are::
- HIV
- human immunodeficiency virus
- AIDS
- acquired immunodeficiency syndrome
- AZT
- 3′-azido-3′-deoxythymidine
- AZT-TP
- 3′-azido-3′-deoxythymidine 5′-triphosphate (tetratriethylammonium salt)
- ddC
- 2′,3′-dideoxycytidine
- NCTR
- National Center for Toxicological Research
- AZTG
- 3′-azido-3′-deoxythymidine-β-d-glucuronide
- AZddU
- 3′-azido-2′,3′-dideoxyuridine
- AZT-MP
- 3′-azido-3′-deoxythymidine 5′-monophosphate (diammonium salt)
- AZT-DP
- 3′-azido-3′-deoxythymidine 5′-diphosphate triethylammonium salt
- [3H]AZT
- [methyl-3H]3′-azido-3′-deoxythymidine
- LSS
- liquid scintillation spectroscopy
- SAX
- strong anion exchange
- CL
- total plasma clearance
- Vdss
- volume of distribution at steady-state
- t1/2
- terminal half-life
- Cpss
- steady-state plasma concentration
- CNS
- central nervous system
- CSF
- cerebrospinal fluid
- Received August 26, 1996.
- Accepted January 13, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
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Transplacental Pharmacokinetics and Fetal Distribution of Azidothymidine, Its Glucuronide, and Phosphorylated Metabolites in Late-Term Rhesus Macaques after Maternal Infusion
