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 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.
Footnotes
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Send reprint requests to: Stanley Vickers, Ph.D., WP 75A-203, Drug Metabolism, Merck Research Laboratories, West Point, PA 19486-0004. E-mail: stanley_vickers{at}merck.com
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↵1 Deceased.
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A preliminary report was presented at the International Society for the Study of Xenobiotics 7th International Meeting (ISSX), October 20–24, 1996, San Diego, California.
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↵3 Metabolism of administered tirofiban in human subjects appears to be limited, and unchanged tirofiban is found in urine and feces (Merck and Co. Aggrastat prescribing information).
- Abbreviations used are::
- HPLC
- high-pressure liquid chromatography
- AUC
- area under the curve
- CYP
- cytochrome P-450
- Vdss
- volume of distribution at steady state
- T1/2
- plasma half-life
- UDPGA
- uridine-5′-diphospho-α-d-glucuronic acid
- Received May 7, 1999.
- Accepted August 10, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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