The pharmacokinetics of cidofovir (HPMPC; (S)-1-[3-hydroxy-2-(phosphonylmethoxy)propyl]cytosine) were examined at five dose levels in three phase I/II studies in a total of 42 human immunodeficiency virus-infected patients (with or without asymptomatic cytomegalovirus infection). Levels of cidofovir in serum following intravenous infusion were dose proportional over the dose range of 1.0 to 10.0 mg/kg of body weight and declined biexponentially with an overall mean +/- standard deviation terminal half-life of 2.6 +/- 1.2 h (n = 25). Approximately 90% of the intravenous dose was recovered unchanged in the urine in 24 h. The overall mean +/- standard deviation total clearance of the drug from serum (148 +/- 25 ml/h/kg; n = 25) approximated renal clearance (129 +/- 42 ml/h/kg; n = 25), which was significantly higher (P < 0.001) than the baseline creatinine clearance in the same patients (83 +/- 21 ml/h/kg; n = 12). These data indicate that active tubular secretion played a significant role in the clearance of cidofovir. The steady-state volume of distribution of cidofovir was approximately 500 ml/kg, suggesting that the drug was distributed in total body water. Repeated dosing with cidofovir at 3.0 and 10.0 mg/kg/week did not alter the pharmacokinetics of the drug. Concomitant administration of intravenous cidofovir and oral probenecid to hydrated patients had no significant effect on the pharmacokinetics of cidofovir at a 3.0-mg/kg dose. At higher cidofovir doses, probenecid appeared to block tubular secretion of cidofovir and reduce its renal clearance to a level approaching glomerular filtration.