RT Journal Article
SR Electronic
T1 Disposition and Metabolism of Tenidap in the Rat
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 140
OP 148
VO 25
IS 2
A1 Hassan G. Fouda
A1 Michael J. Avery
A1 Deepak Dalvie
A1 Fred C. Falkner
A1 Lawrence S. Melvin
A1 Robert A. Ronfeld
YR 1997
UL http://dmd.aspetjournals.org/content/25/2/140.abstract
AB Tenidap is a new antirheumatic drug currently undergoing clinical evaluation. It inhibits production and activity of cytokines in vivo and causes significant reductions in plasma markers of disease activity in rheumatoid arthritis. After the oral administration of C-14 labeled tenidap, bile, urine and plasma were examined by HPLC and atmospheric pressure tandem mass spectrometry. Label is excreted primarily in bile/feces and the remainder in urine, with good recoveries. Numerous metabolites were identified and the structures of most were confirmed by comparison with authentic synthetic samples. Hydroxylation in several positions on both the oxindole and thienyl rings of tenidap represents the major routes of metabolism; most of these metabolites are subsequently conjugated. The glucuronide of 5′-hydroxytenidap, excreted primarily in bile, is the major metabolite, constituting about one third of the oral dose recovered. Other pathways include dihydroxylation and methoxylation on the thienyl ring. An unusual reduction of hydroxytenidap took place, resulting in the formation of a novel thiolactone analog. Anaerobic incubation with rat cecal contents generated the thiolactone metabolite, suggesting the involvement of gut microflora. The American Society for Pharmacology and Experimental Therapeutics