Pharmacokinetics of 2',3'-dideoxyinosine (BMY-40900), a new anti-human immunodeficiency virus agent, after administration of single intravenous doses to beagle dogs

Abstract

The pharmacokinetics of 2',3'-dideoxyinosine (ddI) were investigated in four adult male beagle dogs that received 15-min infusions of 20-, 50-, and 100-mg/kg doses in a randomized crossover study design. Plasma and urine samples were collected for 10 and 24 h, respectively, and assayed for ddI by high-performance liquid chromatographic methods. The mean maximum concentrations of drug in plasma at the end of 15-min infusions for the 20-, 50-, and 100-mg/kg doses were 33.3, 90.0, and 202 micrograms/ml, respectively. Area under the concentration-time curve data deviated significantly from linearity. The mean total clearance for the low dose (250 ml/min) was significantly greater than that for the high dose (190 ml/min). Renal clearance, which averaged between 98 and 116 ml/min, was dose independent. Renal clearance implied that nonrenal clearance decreased at the high dose (92 ml/min) when compared with that of the low dose (134 ml/min). The average urinary recovery of ddI for the high dose (51.2% of dose) was significantly greater than that for the low dose (45.8%). The volume of distribution at steady state averaged between 7.6 and 10.5 liters and decreased with increasing dose; however, it was not statistically significant. The mean half-life and mean residence time were invariant with respect to dose and averaged between 0.94 and 1.07 h and 0.61 and 0.71 h, respectively. In this dose range, ddI pharmacokinetics are dose dependent.