Placental transfer and fetal disposition of 2',3'-dideoxycytidine and 2',3'-dideoxyinosine in the rhesus monkey.

Division of Neurotoxicology, National Center for Toxicological Research/Food and Drug Administration, Jefferson, AR 72079-9502, USA.
Drug Metabolism and Disposition (Impact Factor: 3.25). 09/1995; 23(8):881-4.
Source: PubMed
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    ABSTRACT: Currently available anti-HIV drugs can be classified into three categories: nucleoside analogue reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, and protease inhibitors. Knowledge of these anti-HIV drugs in various physiological or pharmacokinetic compartments is essential for design and development of drug delivery systems for the treatment of HIV infection. The input and output of anti-HIV drugs in the biological systems are described by their transport and metabolism/elimination in this review. Transport mechanisms of anti-HIV agents across various biological barriers, i.e., gastrointestinal wall, skin, mucosa, blood cerebrospinal barrier, blood–brain barrier, placenta, and cellular membranes, are discussed. Their fates during and after systemic absorption and their metabolism-related drug interactions are reviewed. Many anti-HIV drugs presently marketed in the US bear some significant drawbacks such as relatively short half-life, low bioavailability, poor penetration into the central nervous system, and undesirable side effects. Efforts have been made to design drug delivery systems for the anti-HIV agents to: (1) reduce the dosing frequency; (2) increase the bioavailability and decrease the degradation/metabolism in the gastrointestinal tract; (3) improve the CNS penetration and inhibit the CNS efflux; and (4) deliver them to target cells selectively with minimal side effects. We hope to stimulate further interests in the area of controlled delivery of anti-HIV agents by providing current status of transport and metabolism/elimination of these agents.
    Advanced drug delivery reviews 11/1999; 39(1-39):81-103. DOI:10.1016/S0169-409X(99)00021-6 · 15.04 Impact Factor
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    ABSTRACT: 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. 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. 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. 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.
    Teratology 08/2000; 62(2):93-9. DOI:10.1002/1096-9926(200008)62:2<93::AID-TERA5>3.0.CO;2-M
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    The Hopkins HIV report: a bimonthly newsletter for healthcare providers / Johns Hopkins University AIDS Service 04/2001; 13(2):1, 15.
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