ABSORPTION, DISPOSITION, AND METABOLISM OF [C-14] DIDANOSINE IN THE BEAGLE DOG

The absorption, disposition, and metabolism of didanosine were investi gated in three adult male beagle dogs that received a single iv and po solution dose of 200 mg (ca. 20 mg/kg) of [C-14]didanosine. The dog m odel was ''humanized'' by predosing with pentagastrin (6 mug/kg). The po dose was in buffer, as administered in man. The iv and po sessions were separated by 1 week. Plasma, urine, and feces were collected and assayed for total radioactivity; plasma and urine samples were also an alyzed for intact didanosine using validated HPLC/UV assays. Metabolic profiles of [C-14]didanosine were obtained in plasma and urine. After iv dose, 87% and 0.5% of the administered radioactivity were recovere d in urine and feces within 6 days, respectively; the corresponding re coveries were 84% and 2.1% after po dose. Oral absorption of didanosin e was rapid and complete; but due to first pass metabolism, the absolu te bioavailability of didanosine was 44%. Mean renal clearance of dida nosine (110 ml/min) accounted for about 43% of the total body clearanc e. The mean steady state volume of distribution of didanosine was 9.6 liters. The mean terminal half-life of didanosine was 0.8 hr after iv or po administration. Five putative metabolites, M1 (allantoin), M2, M 3 (uric acid), M4 (hypoxanthine), and M5 (xanthine) of didanosine were observed in plasma and/or urine. The sum of the five metabolites plus unchanged drug accounted for virtually all of the radioactivity in pl asma and urine. Allantoin represented the major metabolite in both pla sma and urine. The extent of metabolism and the proportion of dose exc reted as unchanged didanosine were markedly route dependent. First pas s metabolism of didanosine after a po dose was estimated to be 55% of that absorbed.