1. Academic Validation
  2. Pharmacokinetics and metabolism of 3'-azido-2',3'-dideoxy-5-methylcytidine in rhesus monkeys

Pharmacokinetics and metabolism of 3'-azido-2',3'-dideoxy-5-methylcytidine in rhesus monkeys

  • Drug Metab Dispos. 1993 Sep-Oct;21(5):855-60.
F D Boudinot 1 R F Schinazi K J Doshi H M McClure C K Chu
Affiliations

Affiliation

  • 1 Department of Pharmaceutics, College of Pharmacy, University of Georgia, Athens 30602.
PMID: 7902248
Abstract

3'-Azido-2',3'-dideoxy-5-methylcytidine (AzddMeC, CS-92), a nucleoside analog with structural similarities to both 3'-azido-3'-deoxythymidine (AZT) and 2',3'-dideoxycytidine (ddC), has been shown to be a potent and selective inhibitor of human immunodeficiency virus type 1 in vitro. The pharmacokinetics of AzddMeC were characterized following intravenous and oral administration of 60 mg/kg of the compound to male rhesus monkeys. AZT was found to be a major metabolite of AzddMeC in monkeys. AzddMeC concentrations in serum declined rapidly in a biexponential fashion with the terminal half-life ranging from 0.5 to 1.3 hr. Total clearance of AzddMeC was 2.00 +/- 0.41 liters/hr/kg (mean +/- SD) with the fraction of AzddMeC metabolized to AZT of 0.32 +/- 0.05. Renal excretion of unchanged nucleoside and metabolic deamination yielding AZT were the primary routes of AzddMeC clearance. No glucuronide metabolite of AzddMeC was detected in urine samples, although, AZT-glucuronide was found in urine. The volume of the central compartment of AzddMeC was 0.53 +/- 0.28 liters/kg, the volume of the tissue compartment was 0.37 +/- 0.29 liters/kg, and the steady-state volume of distribution was 0.90 +/- 0.55 liters/kg. Volume of distribution values indicate that AzddMeC distributes extravascularly. The first-order oral absorption rate constant was 0.53 +/- 0.56 hr-1, and oral bioavailability was 26 +/- 13%. Thus, the rate of absorption of AzddMeC after oral administration was variable, and oral bioavailability was incomplete.

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