| Popis: |
The absorption, disposition, and metabolism of didanosine were investigated in three adult male beagle dogs that received a single iv and po solution dose of 200 mg (ca. 20 mg/kg) of [14C]didanosine. The dog model was "humanized" by predosing with pentagastrin (6 micrograms/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 analyzed for intact didanosine using validated HPLC/UV assays. Metabolic profiles of [14C]didanosine were obtained in plasma and urine. After iv dose, 87% and 0.5% of the administered radioactivity were recovered in urine and feces within 6 days, respectively; the corresponding recoveries were 84% and 2.1% after po dose. Oral absorption of didanosine was rapid and complete; but due to first pass metabolism, the absolute bioavailability of didanosine was 44%. Mean renal clearance of didanosine (110 ml/min) accounted for about 43% of the total body clearance. 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, M3 (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 plasma and urine. Allantoin represented the major metabolite in both plasma and urine. The extent of metabolism and the proportion of dose excreted as unchanged didanosine were markedly route dependent.(ABSTRACT TRUNCATED AT 250 WORDS) |
