METABOLISM OF THE PLATELET-ACTIVATING-FACTOR ANTAGONIST (+/-)-TRANS-2-(3'-METHOXY-5'-METHYLSULFONYL-4'-PROPOXYPHENYL)-5-(3'',4'',5''-TRIMETHOXYPHENYL)TETRAHYDROFURAN (L-659,989) IN RHESUS-MONKEYS

1. The plasma concentration, main route of metabolism and excretion of H-3-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 (less-than-or-equal-to 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 (H-3-trans-4'-HP) and the 4'-hydroxy metabolite (H-3-4'-hydroxy) which was isolated as a 2:1 mixture of (+/-)trans:(+/-)cis. 4. Approx. 80% of the radiolabelled dose was excreted equally in the urine and faeces in 96 h, with the largest percentage of the tritiated dose (31 +/- 4%) in the 0-24 h urine. 5. The major metabolites in the excreta were the (+/-)trans/(+/-)cis mixture of H-3-4'-hydroxy and the glucuronide conjugate of H-3-trans-4'-hydroxy. The glucuronide conjugate of H-3-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. H-3-4'-Hydroxy was excreted in both the urine and faeces, accounting for less-than-or-equal-to 0.1% and 7.4% of the dose in i.v. and orally dosed monkeys respectively.