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