Phosphorylation of 3'-azidothymidine in maternal and fetal peripheral blood mononuclear cells during gestation and at term.
The present study compared the phosphorylation rate of 3'-azidothymidine (AZT) in isolated maternal and fetal peripheral blood mononuclear cells (PBMCs) with that in amniocytes obtained during gestation and at term. Maternal PBMCs were isolated from venous blood samples obtained from HIV-seronegative pregnant women during delivery. Immediately after delivery, cord blood specimens were collected, and fetal PBMCs were isolated. In a separate set of experiments, maternal and fetal PBMCs and amniocytes were obtained at 17-21 weeks of gestation. The fresh isolated PBMCs and amniocytes were maintained in RPMI 1640 medium until incubation with 10 microM tritiated AZT (10 microCi/mL). Thereafter, methanolic cell extracts were prepared for determination of AZT phosphates by high-performance liquid chromatography. Fetal PBMCs can efficiently convert AZT to its antivirally active metabolite. There were no significant differences after 6 or 12 hours of incubation with AZT between AZT phosphate levels in maternal and fetal PBMCs isolated at term or at 17-21 weeks of gestation: AZT monophosphate was found to be the major metabolite (about 95%). AZT phosphate levels in the amniocytes were up to sevenfold higher than those in the maternal or fetal PBMCs. These results show that during pregnancy and at term, fetal PBMCs-like maternal PBMCs-are able to take up AZT and to efficiently generate the active metabolite AZT triphosphate. These results are of major significance both in enabling efficient treatment of the fetuses of HIV-infected women and in the prediction and understanding of the efficacy and toxicity of AZT in pregnant women and their fetuses.
Agbaria
Riad
R
Department of Clinical Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel. riad@bgumail.bgu.ac.il
Manor
Esther
E
Barak
Jacob
J
Balzarini
Jan
J
D000650:Amnion / Q000166:cytology / Q000378:metabolism; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000378:metabolism*; D005260:Female; D005312:Fetal Blood / Q000378:metabolism*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism*; D008431:Maternal-Fetal Exchange; D010766:Phosphorylation; D011247:Pregnancy; D011262:Pregnancy Trimester, Second; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage / Q000378:metabolism*; D015215:Zidovudine / Q000008:administration & dosage / Q000378:metabolism*
D019380:Anti-HIV Agents; D018894:Reverse Transcriptase Inhibitors; D015215:Zidovudine