Vol. 27, Issue 11, 1360-1366, November 1999

In Vitro and In Vivo Studies on the Metabolism of Tirofiban

Stanley Vickers, Anthony D. Theoharides,¹ Byron Arison, Suresh K. Balani, Dan Cui, Carol A. Duncan, Joan D. Ellis, Lynn M. Gorham, Stacey L. Polsky, Thomayant Prueksaritanont, Harri G. Ramjit, Donald E. Slaughter, and Kamlesh P. Vyas

Merck Research Laboratories, West Point, Pennsylvania

Tirofiban hydrochloride [L-tyrosine-N-(butylsulfonyl)-O-[4-(4-piperidinebutyl)] monohydrochloride, is a potent and specific fibrinogen receptor antagonist. Radiolabeled tirofiban was synthesized with either ³H-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--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.