In vitro and in vivo studies on the metabolism of tirofiban

Drug Metab Dispos. 1999 Nov;27(11):1360-6.

Abstract

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 (3)H-label incorporated into the phenyl ring of the tyrosinyl residue or (14)C-label in the butane sulfonyl moiety. Neither human liver microsomes nor liver slices metabolized [(14)C]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-alpha-D-glucuronic acid. After a 1 mg/kg i.v. dose of [(14)C]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 [(3)H]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.

MeSH terms

  • Animals
  • Bile / metabolism
  • Dogs
  • Feces
  • Female
  • Fibrinolytic Agents / blood
  • Fibrinolytic Agents / pharmacokinetics*
  • Fibrinolytic Agents / urine
  • Half-Life
  • Humans
  • Male
  • Protein Binding
  • Rats
  • Rats, Sprague-Dawley
  • Tirofiban
  • Tissue Distribution
  • Tyrosine / analogs & derivatives*
  • Tyrosine / blood
  • Tyrosine / pharmacokinetics
  • Tyrosine / urine

Substances

  • Fibrinolytic Agents
  • Tyrosine
  • Tirofiban