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 toxic ity risks low. Azidothymidine (AZT) is currently recommended for pregnant w omen 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'-deoxythymidi ne (d4T) and its active (triphosphorylated) and inactive (thymine and beta- aminoisobutyric acid) metabolites were examined at steady state in late-ter m rhesus macaques. Methods: On the day of the hysterotomy, the mother was administered an intr avenous loading dose of d4T, followed by a 3-hr steady-state intravenous in fusion that also included [H-3]d4T as a tracer. After 3 hr of infusion, the fetus was delivered by cesarean section under halothane/N2O anesthesia. Pl asma, amniotic fluid, and tissues were analyzed for d4T and its inactive me tabolites by HPLC; tissue samples were analyzed for d4T and active (phospho rylated) metabolites by strong anion-exchange HPLC, Results: Maternal steady-state plasma concentrations of d4T were 1-2 mu g/m l, 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 fet al 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 detecte d. Teratology 62:93-99, 2000. Published 2000 Wiley-Liss, Inc.dagger.