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OtherShort Communication

THE EFFECT OF AGE ON SILDENAFIL BIOTRANSFORMATION IN RAT AND MOUSE LIVER MICROSOMES

Jill S. Warrington, Lisa L. Von Moltke, Jerold S. Harmatz, Richard I. Shader and David J. Greenblatt
Drug Metabolism and Disposition November 2003, 31 (11) 1306-1309; DOI: https://doi.org/10.1124/dmd.31.11.1306
Jill S. Warrington
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Lisa L. Von Moltke
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Jerold S. Harmatz
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Richard I. Shader
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David J. Greenblatt
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Abstract

Sildenafil [SIL (Viagra); Pfizer, New York, NY] is a widely prescribed agent for erectile dysfunction in men older than 65 years. The present study evaluated experimental models to assess age-dependent changes in SIL biotransformation using hepatic microsomes from male rats and mice ranging from 6 weeks to 26 months of age. The role of specific isoforms in the conversion of SIL to its primary circulating metabolite, UK-103,320 (piperazine N-desmethyl sildenafil) in the mouse was also investigated using immunoinhibitory antibodies. Although CYP2C11 largely mediated UK-103,320 formation in the rat, UK-103,320 formation was principally inhibited by a CYP3A antibody in the mouse. An age-related decrement in metabolite formation rate was observed for both species, although this effect was more pronounced in the old rats (reduced to 7% of young) than in the old mice (reduced to 51% of young). CYP2C expression was assessed by Western blot analysis in rat and mouse livers. Age-related differences in hepatic CYP3A expression in the mouse were also compared with metabolite formation rates in the mouse model. Decrements with age in CYP2C and -3A expression in the aging rodents paralleled the decrements in SIL biotransformation, suggesting that age-related differences in SIL metabolic rate may, in part, reflect differences in expression. Although the role of specific CYP enzymes and the clearance values for this reaction may differ among species, age-related changes in these rodent models are consistent with the reduced clearance of SIL observed in human studies.

Footnotes

  • ↵1 Abbreviations used are: ED, erectile dysfunction; SIL, sildenafil; UK-103,320, piperazine N-desmethyl sildenafil; HPLC, high-performance liquid chromatography; ANOVA, analysis of variance.

  • This work was supported in part by Grants MH-58435, DA-05258, DA-13209, DK/AI-58496, DA-13834, AG-17880, and RR-00054 from the Department of Health and Human Services.

    • Received March 3, 2003.
    • Accepted August 20, 2003.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 31 (11)
Drug Metabolism and Disposition
Vol. 31, Issue 11
1 Nov 2003
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OtherShort Communication

THE EFFECT OF AGE ON SILDENAFIL BIOTRANSFORMATION IN RAT AND MOUSE LIVER MICROSOMES

Jill S. Warrington, Lisa L. Von Moltke, Jerold S. Harmatz, Richard I. Shader and David J. Greenblatt
Drug Metabolism and Disposition November 1, 2003, 31 (11) 1306-1309; DOI: https://doi.org/10.1124/dmd.31.11.1306

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OtherShort Communication

THE EFFECT OF AGE ON SILDENAFIL BIOTRANSFORMATION IN RAT AND MOUSE LIVER MICROSOMES

Jill S. Warrington, Lisa L. Von Moltke, Jerold S. Harmatz, Richard I. Shader and David J. Greenblatt
Drug Metabolism and Disposition November 1, 2003, 31 (11) 1306-1309; DOI: https://doi.org/10.1124/dmd.31.11.1306
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