Abstract
3′-Azido-2′,3′-dideoxy-5-methylcytidine (AzddMeC) has been shown to have potent activity against human immunodeficiency virus (HIV) in vitro. The purpose of this study was to characterize the pharmacokinetics of AzddMeC in rats. AzddMeC was administered intravenously at doses of 10, 50 and 100 mg kg−1. Plasma and urine AzddMeC concentrations were determined by HPLC. Pharmacokinetic parameters were generated by area/moment analysis. Plasma AzddMeC concentrations after 10mg kg−1 were too low to accurately calculate pharmacokinetic parameters. Following 50 and 100mg kg−1 AzddMeC, plasma drug concentrations declined rapidly with a terminal half-life of approximately 2.5 h. No statistically significant differences were noted in pharmacokinetic parameters between the two higher doses. Total clearance was 1.57 ± 0.33 (mean ± SD) and 1.76 ± 0.32I h−1 kg−1 after 50 and 100 mg kg−1 AzddMeC, respectively. Renal excretion accounted for approximately half of total clearance with 55 ± 11% of the dose recovered as unchanged drug in urine. AzddMeC was not metabolized by deamination to AZT in the rat. No glucuronide metabolite was found in urine. Steady-state volume of distribution of AzddMeC averaged 1.73 ± 0.78 and 1.46 ± 0.441 kg−1 following 50 and 100 mg kg−1, respectively. Thus, the disposition of AzddMeC in rats is independent of dose over the range of 50–100 mg kg−1. The pharmacokinetics of AzddMeC in rats are similar to those of 2′,3′-dideoxycytidine, while the clearance of AzddMeC is 40% less than that of 3′-azido-3′-deoxythymidine.