TY - JOUR T1 - In Vitro and In Vivo Studies on the Metabolism of Tirofiban JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 1360 LP - 1366 VL - 27 IS - 11 AU - Stanley Vickers AU - Anthony D. Theoharides AU - Byron Arison AU - Suresh K. Balani AU - Dan Cui AU - Carol A. Duncan AU - Joan D. Ellis AU - Lynn M. Gorham AU - Stacey L. Polsky AU - Thomayant Prueksaritanont AU - Harri G. Ramjit AU - Donald E. Slaughter AU - Kamlesh P. Vyas Y1 - 1999/11/01 UR - http://dmd.aspetjournals.org/content/27/11/1360.abstract N2 - Tirofiban hydrochloride [l-tyrosine-N-(butylsulfonyl)-O-[4-(4-piperidinebutyl)] monohydrochloride, is a potent and specific fibrinogen receptor antagonist. Radiolabeled tirofiban was synthesized with either3H-label incorporated into the phenyl ring of the tyrosinyl residue or 14C-label in the butane sulfonyl moiety. Neither human liver microsomes nor liver slices metabolized [14C]tirofiban. However, male rat liver microsomes converted a limited amount of the substrate to a more polar metabolite (I) and a relatively less polar metabolite (II). The formation of I was sex dependent and resulted from an O-dealkylation reaction catalyzed by CYP3A2. Metabolite II was identified as a 2-piperidone analog of tirofiban. There was no evidence for Phase II biotransformation of tirofiban by microsomes fortified with uridine-5′-diphospho-α-d-glucuronic acid. After a 1 mg/kg i.v. dose of [14C]tirofiban, recoveries of radioactivity in rat urine and bile were 23 and 73%, respectively. Metabolite I and unchanged tirofiban represented 70 and 30% of the urinary radioactivity, respectively. Tirofiban represented >90% of the biliary radioactivity. At least three minor biliary metabolites represented the remainder of the radioactivity. One of them was identified as I. Another was identified as II. When dogs received 1 mg/kg i.v. of [3H]tirofiban, most of the radioactivity was recovered in the feces as unchanged tirofiban. The plasma half-life of tirofiban was short in both rats and dogs, and tirofiban was not concentrated in tissues other than those of the vasculature and excretory organs. The American Society for Pharmacology and Experimental Therapeutics ER -