Transplacental pharmacokinetics and fetal distribution of 2', 3'-didehydro-3'-deoxythymidine (d4T) and its metabolites in late-term rhesus macaques.
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.
Division of Neurotoxicology, National Center for Toxicological Research/FDA, Jefferson, Arkansas 72079-9502, USA. tucker.patterson@mail.state.ar.us
T A
TA
Patterson
Z K
ZK
Binienda
G D
GD
Newport
G W
GW
Lipe
M P
MP
Gillam
W
W
Slikker
J A
JA
Sandberg
D000621:Aminoisobutyric Acids / Q000493:pharmacokinetics; D000818:Animals; D019380:Anti-HIV Agents / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D005260:Female; D005333:Fetus / Q000378:metabolism*; D007668:Kidney / Q000187:drug effects / Q000196:embryology; D008253:Macaca mulatta / Q000196:embryology*; D008431:Maternal-Fetal Exchange; D010920:Placenta / Q000187:drug effects*; D011247:Pregnancy; D018119:Stavudine / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D013941:Thymine / Q000493:pharmacokinetics; D013997:Time Factors; D014018:Tissue Distribution
D000621:Aminoisobutyric Acids; D019380:Anti-HIV Agents; D018119:Stavudine; D013941:Thymine; C033435:3-aminoisobutyric acid