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Research ArticleToxicology

Influence of Dosing Time on the Efficacy and Safety of Finasteride in Rats

Masafumi Kumazaki, Hitoshi Ando, Kentarou Ushijima, Tomohiro Maekawa, Yuya Motosugi, Makoto Takada, Masato Tateishi and Akio Fujimura
Journal of Pharmacology and Experimental Therapeutics August 2011, 338 (2) 718-723; DOI: https://doi.org/10.1124/jpet.111.182865
Masafumi Kumazaki
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Hitoshi Ando
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Kentarou Ushijima
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Tomohiro Maekawa
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Yuya Motosugi
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Makoto Takada
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Masato Tateishi
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Akio Fujimura
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Abstract

Finasteride (FIN), a widely used medication for the treatment of androgen-dependent diseases, blocks the conversion of testosterone to a more potent androgen, dihydrotestosterone (DHT). In this study, we investigated a dosing time-dependent effect and safety of FIN in rats. Androgen receptor (AR) mRNA and nuclear protein levels exhibited clear daily rhythms with the peak during the dark period in the prostate and during the light period in the liver. Repeated oral administration of FIN (5 or 100 mg/kg) at 3 h after lights on (HALO) for 2 weeks decreased serum DHT concentration throughout a 24-h period, whereas the dosing of the agent at 15 HALO decreased its level only transiently even in the higher dose group. FIN caused laboratory abnormalities in the 3 HALO group but not in the 15 HALO group. However, the effect of FIN on the prostate weight was not influenced by the dosing time. These results suggest that the safety, but not effect, of FIN depends on its dosing time in rats. The dosing of FIN in the active period might be a rational dosage regimen, which is needed to be confirmed in human subjects.

Footnotes

  • This work was supported by Merck & Co., Inc.; and the Japan Keirin Association through promotion funds from Keirin Race [Grant 901811].

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

    doi:10.1124/jpet.111.182865.

  • ↵Embedded Image The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.

  • ABBREVIATIONS:

    FIN
    finasteride
    DHT
    dihydrotestosterone
    BPH
    benign prostatic hyperplasia
    AR
    androgen receptor
    GAPDH
    glyceraldehyde-3-phosphate dehydrogenase
    HALO
    hours after light on
    ALT
    alanine aminotransferase
    IS
    internal standard
    HSP90
    heat shock protein 90
    PCR
    polymerase chain reaction.

  • Received April 10, 2011.
  • Accepted May 20, 2011.
  • Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 338 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 338, Issue 2
1 Aug 2011
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Research ArticleToxicology

Influence of Dosing Time on the Efficacy and Safety of Finasteride in Rats

Masafumi Kumazaki, Hitoshi Ando, Kentarou Ushijima, Tomohiro Maekawa, Yuya Motosugi, Makoto Takada, Masato Tateishi and Akio Fujimura
Journal of Pharmacology and Experimental Therapeutics August 1, 2011, 338 (2) 718-723; DOI: https://doi.org/10.1124/jpet.111.182865

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Research ArticleToxicology

Influence of Dosing Time on the Efficacy and Safety of Finasteride in Rats

Masafumi Kumazaki, Hitoshi Ando, Kentarou Ushijima, Tomohiro Maekawa, Yuya Motosugi, Makoto Takada, Masato Tateishi and Akio Fujimura
Journal of Pharmacology and Experimental Therapeutics August 1, 2011, 338 (2) 718-723; DOI: https://doi.org/10.1124/jpet.111.182865
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