Dose-Dependent Pharmacokinetics of 3′-azido-2′,3′-dideoxyuridine in Rats

Abstract

The pharmacokinetics of 3′-azido-2′,3′-dideoxyuridine (AzddU; CS-87), an inhibitor of human immunodeficiency virus (HIV) replication in vitro, were characterized in rats. AzddU was administered intravenously at doses of 10, 50, 100 and 250mgkg−1. Plasma and urine AzddU concentrations were measured by HPLC. Plasma AzddU concentrations declined in a biexponential fashion with a terminal half-life of approximately 1.5h. The disposition of AzddU was independent of dose over the dosage range of 10–100mgkg−1; however, the pharmacokinetics of the nucleoside exhibited non-linearities after 250mgkg−1. Over the dose range of 10–100mgkg−1 AzddU, total clearance and renal clearance averaged 2.13lh−1kg−1 and 1.46lh−1kg−1, respectively. Total clearance was significantly lower after 250mgkg−1 ( CIT = 1.32lh−1kg−1) owing to a decreased renal clearance ( CIR = 0.69lh−1kg−1) of AzddU. Renal clearance exceeded glomerular filtration rate, indicating that active renal tubular secretion was involved in the renal excretion of the compound. The maximum transport capacity ( Tmax) and the Michaelis–Menton constant ( Km) for the tubular secretion mechanism were 142.2mg h−1 and 60.4mg l−1, respectively. The high values for Tmax and Km explain the high renal clearance of AzddU and the linearity of renal excretion over a wide range of drug concentrations. However, at very high AzddU concentrations active tubular secretion is saturable. Nonrenal clearance was independent of dose with a mean value of 0.66lh−1kg−1. Steady-state volume of distribution was similar at all doses averaging 1.05lkg−1. Thus, the disposition of AzddU is linear over the dose range of 10–100mgkg−1, but becomes dose dependent with decreases in renal and total clearances after 250mgkg−1 AzddU.