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

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 (CI_T = 1.32lh⁻¹kg⁻¹) owing to a decreased renal clearance (CI_R = 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 (T_max) and the Michaelis–Menton constant (K_m) for the tubular secretion mechanism were 142.2mg h⁻¹ and 60.4mg l⁻¹, respectively. The high values for T_max and K_m 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.