Abstract
1. The plasma concentration, main route of metabolism and excretion of 3H-L-659,989 were studied in male and female rhesus monkeys by dosing either i.v. or orally at 10 mg/kg.
2. The percentage of the AUC for the plasma radioactivity concentration-time curve of oral vs i.v. dosed monkeys was 78% for males and 90% for females, indicating that the dose was well absorbed.
3. The bioavailability of the drug was low (≤10%) for all monkeys, probably due to rapid first pass metabolism. The drug was metabolized predominantly at the C-4′-propoxy side-chain. The two major plasma metabolites were identified as the 4′-2-(hydroxy)propoxy metabolite (3H-trans-4′-HP) and the 4′-hydroxy metabolite (3H-4′-hydroxy) which was isolated as a 2:1 mixture of (±)trans:(±)cis.
4. Approx, 80% of the radiolabelied dose was excreted equally in the urine and faeces in 96h, with the largest percentage of the Initiated dose (31.4%) in the 0-24h urine.
5. The major metabolites in the excreta were the (±)trans(±)cis mixture of 3H-4′-hydroxy and the glucuronide conjugate of 3H-trans-4′-hydroxy. The glucuronide conjugate of 3H-trans-4′-hydroxy was excreted in the urine of i.v. and orally dosed monkeys and represented an average of 21% and 5.1% of the dose, respectively. 3H-4′-Hydroxy was excreted in both the urine and faeces, accounting for. 0.1% and 7.4% of the dose in i.v. and orally dosed monkeys, respectively.