The pharmacokinetics of 2',3'-dideoxycytidine (DDC) was characterized after iv administration of a high dose (500 mg/kg) of DDC to rats. The high dose was administered to optimally characterize plasma DDC concentration and urinary excretion rate versus time profiles. Drug concentrations in plasma and urine were determined by HPLC. Plasma DDC concentrations and DDC urinary excretion rates as a function of time were fitted simultaneously to a two-compartment model. Drug concentrations in plasma and urinary excretion rates declined in parallel with a terminal half-life of 1.29 +/- 0.07 h (mean +/- SD). Total, renal, and nonrenal clearances were 1.48 +/- 0.15, 0.73 +/- 0.38, and 0.75 +/- 0.36 L/h/kg, respectively. Renal clearance exceeds glomerular filtration rate in the rat, indicating that DDC undergoes active renal tubular secretion. The unbound secretory intrinsic clearance for DDC renal excretion was moderate, with a value of 0.4 L/h. The steady-state volume of distribution of DDC was 1.25 +/- 0.13 L/kg. Pharmacokinetic parameters after iv administration of 500 mg/kg of DDC were virtually identical to those reported previously after administration of 10-200 mg/kg of the nucleoside to rats. Thus, the disposition of DDC in the rat is independent of dose over a range of 10 to 500 mg/kg. High doses of DDC can be administered to rats to allow for complete characterization of the disposition pattern of the drug without complexities due to any nonlinearity.