The time of administration of 3'-azido-3'-deoxythymidine (AZT) determines its toxicity (Meeting abstract).

Important note: Information in this article was accurate in 1993. The state of the art may have changed since the publication date.

The time of administration of 3'-azido-3'-deoxythymidine (AZT) determines its toxicity (Meeting abstract).

Proc Annu Meet Am Assoc Cancer Res; 34:A1666 1993. Unique Identifier : AIDSLINE ICDB/93692607
Zhang R; Lu Z; Guttmann R; Diasio RB; Dept. of Pharmacology, Univ. of Alabama, Birmingham, AL 35294

Abstract: AZT is the most widely used drug in the treatment of AIDS. Its major drug-related toxicity is bone marrow suppression, which limits the dose of AZT that can be used. It is essential that AZT be phosphorylated to AZT-MP, AZT-DP, and AZT-TP for antiviral effect. We have recently demonstrated that thymidine kinase (TK), the initial enzyme in AZT anabolism, follows a circadian pattern in rat bone marrow. The present study was undertaken to determine if AZT toxicity is related to the time of its administration and if the variation in toxicity is correlated with the circadian variation in TK activity. Male Sprague-Dawley rats (40-50 g) were housed under standardized conditions of light and dark (lights-on 6:00-18:00 and lights-off 18:00-6:00) for 4 wk. The animals were randomly divided into 7 groups: one group as control; the other groups were given IP bolus AZT at the same dose of 700 mg/kg body wt at various times (4:00, 8:00, 12:00, 16:00, 20:00, 24:00). AZT-related toxic effects including bone marrow toxicity differed significantly among the treatment groups, depending on the time of AZT administration (ANOVA and Cosinor analysis, p greater than 0.001). The least toxicity was observed in rats receiving AZT at 16:00, the greatest toxicity at 4:00. To verify these results, we administered AZT at an LD50 (1,500 mg/kg) to two groups of rats: one at 12:00 and the other at 24:00. AZT lethality was significantly higher in rats receiving AZT at 24:00. The variation in AZT toxicity was consistent with the circadian variation in TK activity in bone marrow (peak activity at 4:00 and trough activity at 16:00), suggesting that the circadian variation in TK activity may be the biochemical basis for the observed circadian variation in AZT toxicity.

Keywords: Animal Bone Marrow/DRUG EFFECTS Circadian Rhythm Male Rats Rats, Sprague-Dawley Zidovudine/*ADMINISTRATION & DOSAGE/ADVERSE EFFECTS ABSTRACT
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