Disposition and irreversible plasma protein binding of tolmetin in humans.
The pharmacokinetics and irreversible plasma protein binding of tolmetin were studied in six healthy subjects after the administration of a single, 400 mg dose of tolmetin. With HPLC analysis, tolmetin, tolmetin glucuronide, and the isomers of tolmetin glucuronide, which result from intramolecular acyl migration in vivo, were detected in the plasma up to 4 hours after administration, whereas these conjugates were present in the urine up to 24 hours. Irreversible binding of tolmetin to plasma proteins occurred in all subjects. Irreversible binding exhibited a better correlation with exposure to tolmetin glucuronide (r = 0.5618) and the isomers of tolmetin glucuronide (r = 0.8200) than with exposure to tolmetin (-0.3635). This is consistent with the hypothesis that covalent binding occurs via the acyl glucuronide.
Hyneck
M L
ML
Department of Pharmacy, School of Pharmacy, University of California, San Francisco 94143-0446.
Smith
P C
PC
Munafo
A
A
McDonagh
A F
AF
Benet
L Z
LZ
D000328:Adult; D001682:Biological Availability; D001798:Blood Proteins / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D003627:Data Interpretation, Statistical; D005260:Female; D006207:Half-Life; D006801:Humans; D008297:Male; D011758:Pyrroles / Q000493:pharmacokinetics*; D014046:Tolmetin / Q000031:analogs & derivatives / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics* / Q000652:urine
D001798:Blood Proteins; D011758:Pyrroles; C020402:1-methyl-5-(4-carboxybenzoyl)-1H-pyrrole-2-acetic acid; C056583:tolmetin glucuronide; D014046:Tolmetin