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Research ArticleArticle

In Vitro and In Vivo Studies on the Metabolism of Tirofiban

Stanley Vickers, Anthony D. Theoharides, 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
Drug Metabolism and Disposition November 1999, 27 (11) 1360-1366;
Stanley Vickers
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Anthony D. Theoharides
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Byron Arison
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Suresh K. Balani
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Dan Cui
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Carol A. Duncan
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Joan D. Ellis
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Lynn M. Gorham
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Stacey L. Polsky
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Thomayant Prueksaritanont
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Harri G. Ramjit
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Donald E. Slaughter
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Kamlesh P. Vyas
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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

  • 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

  • ↵1 Deceased.

  • 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.

  • ↵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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Drug Metabolism and Disposition: 27 (11)
Drug Metabolism and Disposition
Vol. 27, Issue 11
1 Nov 1999
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Research ArticleArticle

In Vitro and In Vivo Studies on the Metabolism of Tirofiban

Stanley Vickers, Anthony D. Theoharides, 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
Drug Metabolism and Disposition November 1, 1999, 27 (11) 1360-1366;

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Research ArticleArticle

In Vitro and In Vivo Studies on the Metabolism of Tirofiban

Stanley Vickers, Anthony D. Theoharides, 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
Drug Metabolism and Disposition November 1, 1999, 27 (11) 1360-1366;
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