Pharmacokinetics and metabolism of 3'-azido-2',3'-dideoxy-5-methylcytidine in rhesus monkeys.
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.
Boudinot
F D
FD
Department of Pharmaceutics, College of Pharmacy, University of Georgia, Athens 30602.
Schinazi
R F
RF
Doshi
K J
KJ
McClure
H M
HM
Chu
C K
CK
D000284:Administration, Oral; D000818:Animals; D000998:Antiviral Agents / Q000378:metabolism* / Q000493:pharmacokinetics*; D001386:Azides / Q000378:metabolism* / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D007275:Injections, Intravenous; D008253:Macaca mulatta; D008297:Male; D008954:Models, Biological; D016047:Zalcitabine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics
D000998:Antiviral Agents; D001386:Azides; D016047:Zalcitabine; C057658:3'-azido-2',3'-dideoxy-5-methylcytidine