Biochemistry and pharmacokinetics of potent non-steroidal cytochrome P450(17alpha) inhibitors
| Autor: | Ben P. Haynes, Mitchell Dowsett, P.M. Goddard, Ferdinand Chan, Michael Jarman, Gerard A. Potter, S.E. Barrie |
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| Rok vydání: | 1997 |
| Předmět: |
Male
Cytochrome Pyridines Endocrinology Diabetes and Metabolism Clinical Biochemistry Adamantane Mice Inbred Strains Pharmacology Biochemistry Mice Endocrinology Pharmacokinetics In vivo Testis Animals Testosterone Tissue Distribution Molecular Biology Progesterone chemistry.chemical_classification biology Cytochrome P450 Steroid 17-alpha-Hydroxylase Biological activity Cell Biology Enzyme Ketoconazole chemistry Enzyme inhibitor Toxicity biology.protein Molecular Medicine Propionates Half-Life |
| Zdroj: | The Journal of steroid biochemistry and molecular biology. 60(5-6) |
| ISSN: | 0960-0760 |
| Popis: | Two potent non-steroidal inhibitors (CB7645 and CB7661) of human cytochrome P450 17α were tested for in vivo activity in WHT mice. There were no signs of toxicity, but there was no effect on the androgen-dependent organs. The pharmacokinetics and biochemistry of the compounds in mice were investigated. Following i.p. administration of 0.5 mmol/kg of CB7645 and CB7661, peak plasma levels of 13.4 and 3.4 μM, respectively, occurred after 2–4 h, both compounds were cleared rapidly (terminal half-lives 2.7 and 3.3 h, respectively) and neither was detectable at 24 h. CB7645 produced some decrease in plasma testosterone at 4 h, but this was not sustained. When tested in vitro against the WHT testicular enzyme, the CB7645 and CB7661 were competitive inhibitors with K i values of 10 and 13 nM, respectively. However, the K m for the substrate progesterone was lower at 4.3 nM. These data indicate that, for effective and continuous inhibition of the murine cytochrome P450 17α enzyme, higher peak levels of the compounds would be required, and these levels would need to be maintained throughout the treatment period. |
| Databáze: | OpenAIRE |
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