Document Detail


Transplacental pharmacokinetics and fetal distribution of 2', 3'-didehydro-3'-deoxythymidine (d4T) and its metabolites in late-term rhesus macaques.
MedLine Citation:
PMID:  10931506     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND: The overall goal of human immunodeficiency virus (HIV) therapy during pregnancy is to maintain maternal health and reduce the probability of vertical transmission during gestation and delivery, while keeping toxicity risks low. Azidothymidine (AZT) is currently recommended for pregnant women infected with HIV; however, many pregnant women are unable to tolerate AZT because of toxicity. In the present study, the placental transfer and fetal accumulation of the anti-HIV compound 2',3'-didehydro-3'-deoxythymidine (d4T) and its active (triphosphorylated) and inactive (thymine and beta-aminoisobutyric acid) metabolites were examined at steady state in late-term rhesus macaques. METHODS: On the day of the hysterotomy, the mother was administered an intravenous loading dose of d4T, followed by a 3-hr steady-state intravenous infusion that also included [(3)H]d4T as a tracer. After 3 hr of infusion, the fetus was delivered by cesarean section under halothane/N(2)O anesthesia. Plasma, amniotic fluid, and tissues were analyzed for d4T and its inactive metabolites by HPLC; tissue samples were analyzed for d4T and active (phosphorylated) metabolites by strong anion-exchange HPLC. RESULTS: Maternal steady-state plasma concentrations of d4T were 1-2 microg/ml, with a fetal-to-maternal plasma ratio of 0.85 +/- 0.09. The fetal tissue distribution of radioactivity was highest in the kidney and lowest in the brain. D4T, thymine, and beta-aminoisobutyric acid were detected in all fetal tissues examined. CONCLUSIONS: Our data indicate that d4T readily crosses the placenta and is present in the fetus as parent compound or its inactive metabolites after maternal infusion. Although fetal plasma concentrations of d4T were similar to clinical d4T concentrations, no phosphorylated metabolites were detected. Teratology 62:93-99, 2000. Published 2000 Wiley-Liss, Inc.
Authors:
T A Patterson; Z K Binienda; G D Newport; G W Lipe; M P Gillam; W Slikker; J A Sandberg
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Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Teratology     Volume:  62     ISSN:  0040-3709     ISO Abbreviation:  Teratology     Publication Date:  2000 Aug 
Date Detail:
Created Date:  2000-10-02     Completed Date:  2000-10-02     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  0153257     Medline TA:  Teratology     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  93-9     Citation Subset:  IM; X    
Affiliation:
Division of Neurotoxicology, National Center for Toxicological Research/FDA, Jefferson, Arkansas 72079-9502, USA. tucker.patterson@mail.state.ar.us
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MeSH Terms
Descriptor/Qualifier:
Aminoisobutyric Acids / pharmacokinetics
Animals
Anti-HIV Agents / blood,  metabolism,  pharmacokinetics*
Chromatography, High Pressure Liquid
Female
Fetus / metabolism*
Kidney / drug effects,  embryology
Macaca mulatta / embryology*
Maternal-Fetal Exchange
Placenta / drug effects*
Pregnancy
Stavudine / blood,  metabolism,  pharmacokinetics*
Thymine / pharmacokinetics
Time Factors
Tissue Distribution
Grant Support
ID/Acronym/Agency:
IAG Y01-ES-10187/ES/NIEHS NIH HHS
Chemical
Reg. No./Substance:
0/Aminoisobutyric Acids; 0/Anti-HIV Agents; 144-90-1/3-aminoisobutyric acid; 3056-17-5/Stavudine; 65-71-4/Thymine

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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