Metabolism of the platelet-activating factor antagonist (+/-)-trans-2-(3'-methoxy-5'-methylsulphonyl-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 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 (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 (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 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 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 less than or equal to 0.1% and 7.4% of the dose in i.v. and orally dosed monkeys, respectively.
Thomson
K L
KL
Department of Medicinal Chemical Research, Merck Sharp & Dohme Research Laboratories, Rahway, NJ 07065-0900.
Chang
M N
MN
Bugianesi
R L
RL
Ponpipom
M M
MM
Arison
B H
BH
Hucker
H B
HB
Sweeney
B M
BM
White
S D
SD
Chabala
J C
JC
D000818:Animals; D001682:Biological Availability; D001711:Biotransformation; D005260:Female; D005663:Furans / Q000493:pharmacokinetics*; D007536:Isomerism; D008253:Macaca mulatta; D008297:Male; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors*; D012737:Sex Factors; D014316:Tritium
D005663:Furans; D010972:Platelet Activating Factor; D014316:Tritium; C054893:L 659989