Metabolism of finasteride in rat hepatic microsomes: age and sex differences and effects of P450 inducers.
1. The age- and sex-related metabolism of finasteride and the effects of P450 inducers and inhibitors were investigated using rat hepatic microsomes. 2. No marked age difference (3-13 weeks) in the rates of finasteride disappearance and the formation of 1 (omega-hydroxyfinasteride) and 4 (6 alpha-OH finasteride) was observed in the male rat. Whereas the rate of 1 formation remained about the same in male rat aged 1 year as compared with rat aged 7 weeks, a 21 and 45% decrease in the rate of finasteride disappearance and 4 formation, respectively, were observed. 3. The rates of finasteride disappearance and metabolite formation 1 and 4 in the female rat decreased with an increase in age (3-7 weeks). Metabolite 4 was hardly formed by the hepatic microsomes from the female rat at 7 weeks of age. 4. Hepatic microsomes from the male rat treated with phenobarbital (PB) and dexamethasone (Dex) increased the rate of the finasteride disappearance (PB, 5.5-fold; Dex, 11.6-fold), whereas no increase in this activity was observed after administration of beta-naphthoflavone (BNF). Similarly, pretreatment of the female rat with PB and Dex resulted in increases of 26.6 and 8.4-fold in the rate of finasteride disappearance, respectively, whereas no inductive effect on this activity was observed in the BNF-treated female rat. 5. These observations suggest that finasteride is metabolized by P4502B, P4502C, and P4503A subfamilies in the male rat and by P4502B and P4502C subfamilies in the female rat.
Ishii
Y
Y
Drug Metabolism, Development Research Laboratories, Banyu Pharmaceutical Co., Ltd, Saitama, Japan.
Mukoyama
H
H
Hata
S
S
D000375:Aging / Q000378:metabolism; D000818:Animals; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000378:metabolism*; D004790:Enzyme Induction; D005260:Female; D018120:Finasteride / Q000378:metabolism*; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012737:Sex Factors
D065607:Cytochrome P-450 Enzyme Inhibitors; D007527:Isoenzymes; D018120:Finasteride; D003577:Cytochrome P-450 Enzyme System