Abstract
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.
Footnotes
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Send reprint requests to: Dr. Hassan G. Fouda, Drug Metabolism Department, Pfizer, Inc., Groton, CT 06340.
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↵2 Tenidap exists in solution and in the solid state in its enolic form at the C3 carbonyl and the form being studied clinically is the sodium salt of the enol. Nevertheless, the keto form of tenidap and its metabolites is used in this report, since fragmentation during mass spectral analysis (gas phase, elevated energy state) is more easily rationalized from this form.
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↵3 N. Castagnoli, Jr., personal communication.
- Abbreviations used are::
- NSAID
- nonsteroidal antiinflammatory drug
- ICP
- ion current profile
- SIM
- selected ion monitoring
- MRM
- multiple reaction monitoring
- CID
- collision-induced dissociation
- The American Society for Pharmacology and Experimental Therapeutics
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