CATABOLISM OF 2',3'-DIDEHYDRO-2',3'-DIDEOXYTHYMIDINE (D4T) IN ISOLATED HEPATOCYTES AND IN RHESUS MONKEYS (MEETING ABSTRACT)

Important note: Information in this article was accurate in 1992. The state of the art may have changed since the publication date.

CATABOLISM OF 2',3'-DIDEHYDRO-2',3'-DIDEOXYTHYMIDINE (D4T) IN ISOLATED HEPATOCYTES AND IN RHESUS MONKEYS (MEETING ABSTRACT)

Proc Annu Meet Am Assoc Cancer Res; 33:A3253 1992. Unique Identifier : AIDSLINE ICDB/92685792
Sommadossi JP; Zhou Z; Hitchcock MJ; McClure HM; el Kouni M; Cretton E; Univ. of Alabama at Birmingham, Birmingham, AL 35294

Abstract: The present study evaluated the in vitro and in vivo catabolic fate of D4T, a novel anti-HIV agent. Following a 2-hr exposure of hepatocytes to 10 uM [3H]D4T, the predominant intracellular catabolite was beta-aminoisobutyric acid (BAIBA), representing 16% of the radioactivity by 90 min. Thymine levels decreased to 0.5% by 90 min. Increasing levels of tritiated water [3H2O] were also detected. In the presence of 1 mM thymine, 10 uM BBU (an inhibitor of dihydrouracil dehydrogenase) BAIBA was inhibited by 100% and 50%, respectively. Following sc administration of 25 mg/kg [3H]D4T in rhesus monkeys, a similar catabolic profile was observed. The D4T Cmax averaged 14.3 ug/ml with an apparent plasma T1/2 of about 1 hr. Levels of thymine and BAIBA were detected in biological fluids as early as 0.5 hr after administration, with plasma Cmax values averaging 0.45 ug/ml and 0.60 ug/ml, respectively. In addition, 3H20 was also detected. Urinary recovery of total radioactivity was approx 50% 24 hr after administration. Preliminary studies showed that D4T is a substrate for purified human thymidine phosphorylase. These results suggest that D4T catabolism involves a sequential degradation to thymine and BAIBA.

Keywords: Aminoisobutyric Acids/METABOLISM Animal Dideoxynucleosides/*METABOLISM Human Liver/CYTOLOGY/*METABOLISM Macaca mulatta Substrate Specificity Thymidine Phosphorylase/METABOLISM Thymine/METABOLISM ABSTRACT
921230
M92C5371

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