In vitro and in vivo studies on the metabolism of tirofiban

Tirofiban hydrochloride [L-tyrosine-N-(butylsulfonyl)-O-[4-(4-piperidinebut yl)] monohydrochloride, is a potent and specific fibrinogen receptor antago nist. Radiolabeled tirofiban was synthesized with either H-3-label incorpor ated into the phenyl ring of the tyrosinyl residue or C-14-label in the but ane sulfonyl moiety. Neither human liver microsomes nor liver slices metabo lized [C-14]tirofiban. However, male rat liver microsomes converted a limit ed 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 result ed from an O-dealkylation reaction catalyzed by CYP3A2. Metabolite II was i dentified as a 2-piperidone analog of tirofiban. There was no evidence for Phase II biotransformation of tirofiban by microsomes fortified with uridin e-5'-diphospho-alpha-D-glucuronic acid. After a 1 mg/kg i.v. dose of [C-14] tirofiban, recoveries of radioactivity in rat urine and bile were 23 and 7 3%, respectively. Metabolite I and unchanged tirofiban represented 70 and 3 0% of the urinary radioactivity, respectively. Tirofiban represented >90% o f the biliary radioactivity. At least three minor biliary metabolites repre sented 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 [H-3]tiro fiban, most of the radioactivity was recovered in the feces as unchanged ti rofiban. 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 vasc ulature and excretory organs.