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Research ArticleArticle

Identification of Cytochromes P450 Involved in the Human Liver Microsomal Metabolism of the Thromboxane A2 Inhibitor Seratrodast (ABT-001)

Gondi N. Kumar, Erik Dubberke, A. David Rodrigues, Ellen Roberts and Jon F. Dennisen
Drug Metabolism and Disposition January 1997, 25 (1) 110-115;
Gondi N. Kumar
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Erik Dubberke
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A. David Rodrigues
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Ellen Roberts
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Jon F. Dennisen
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Abstract

Seratrodast (ABT-001, AA-2414) undergoes cytochrome P450 (CYP)-dependent metabolism to a major (5-methylhydroxy seratrodast; 5-HOS) and a minor 4′-hydroxy seratrodast metabolite in human liver microsomes. The mean apparent Km andVmax for the formation of 5-HOS were 15.5 μM and 589.0 pmol 5-HOS formed/mg protein/min, respectively. Chemical inhibition using isoform-selective CYP inhibitors, correlation of 5-HOS formation with several isoform-specific CYP activities in a panel of liver microsomes, metabolism by microsomes derived from CYP cDNA-expressed B-lymphoblastoid cells, and immunoinhibition by isoform-specific anti-CYP antibodies indicated that 5-HOS formation is catalyzed by CYP3A and CYP2C9/10, with a minor contribution from CYP2C8 and CYP2C19. At clinically relevant concentrations, seratrodast was found to inhibit tolbutamide methylhydroxylation (IC50 = 60 μM), (S)-mephenytoin 4′-hydroxylation (IC50 = 50 μM), and coumarin 7-hydroxylation (IC50 = 95 μM), indicating the potential for significant clinical interactions. The inducers of CYP3A and/or CYP2C9 (e.g. rifampicin and phenytoin) are likely to alter the disposition of seratrodast.

Footnotes

  • Send reprint requests to: Dr. Gondi N. Kumar, Biotransformation Department, D-46V, AP9, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064-3500.

  • This study was supported by TAP Holdings, Inc. E.D. was the recipient of an Abbott Summer (1995) Research Internship.

  • ↵2 Dr. J. M. Lasker, personal communication, 1996.

  • ↵3 Dr. E. Samara, personal communication, 1996.

  • Abbreviations used are::
    5-HOS
    5-methylhydroxy seratrodast
    4′-HOS
    4′-hydroxy seratrodast
    MTT
    3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
    CYP
    cytochrome P450
    IgG
    immunoglobulin G
    CLint
    intrinsic clearance
    Vmax
    maximum initial velocity
    Km
    Michaelis constant
    IC50
    concentration that inhibited 50% of the activity
    • Received June 28, 1996.
    • Accepted October 10, 1996.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition
Vol. 25, Issue 1
1 Jan 1997
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Research ArticleArticle

Identification of Cytochromes P450 Involved in the Human Liver Microsomal Metabolism of the Thromboxane A2 Inhibitor Seratrodast (ABT-001)

Gondi N. Kumar, Erik Dubberke, A. David Rodrigues, Ellen Roberts and Jon F. Dennisen
Drug Metabolism and Disposition January 1, 1997, 25 (1) 110-115;

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Research ArticleArticle

Identification of Cytochromes P450 Involved in the Human Liver Microsomal Metabolism of the Thromboxane A2 Inhibitor Seratrodast (ABT-001)

Gondi N. Kumar, Erik Dubberke, A. David Rodrigues, Ellen Roberts and Jon F. Dennisen
Drug Metabolism and Disposition January 1, 1997, 25 (1) 110-115;
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