Drug Metab Dispos. 2004 Oct;32(10):1121-31. Epub 2004 Jul 8.
Role of itraconazole metabolites in CYP3A4 inhibition.
Isoherranen N, Kunze KL, Allen KE, Nelson WL, Thummel KE.
University of Washington, Department of Pharmaceutics, H272 Health Sciences Building.
Выводы: ИТК является мощным ингибитором изофермента системы P-450 -CYP3A4, его метаболиты являются еще большими ингибиторами итого изофермента (исследование in vivo).
Characterization of testosterone 11 beta-hydroxylation catalyzed by human liver microsomal cytochromes P450.
Biological Engineering Division, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.
A combination of accelerator mass spectrometry (AMS) and liquid chromatography-tandem mass spectrometry has been used to clarify some new aspects of testosterone metabolism. The main pathway of testosterone oxidative metabolism by human liver microsomes is the formation of 1beta-, 2alpha-/beta-, 6beta-, 15beta-, and 16beta-hydroxytestosterones, mainly catalyzed by cytochromes P450 2C9, 2C19, and 3A4. We now report the first determination that 11beta-hydroxytestosterone (11beta-OHT) can also be formed by human liver microsomal fractions. The structures of five hydroxylated metabolites of testosterone (2beta-, 6beta-, 11beta-, 15beta-, and 16beta-OHT) and the C-17 oxidative metabolite androstenedione were determined by liquid chromatography with UV detection at 240 nm and liquid chromatography-tandem mass spectrometry. Corresponding results were obtained by high-performance liquid chromatography-AMS analysis of incubations of [4-14C]testosterone with human liver microsomes. 6beta-Hydroxylation was always the dominant metabolic pathway, but 2beta-, 15beta-, and 16beta-OHT, and androstenedione were also formed. The previously undetected hydroxytestosterone, 11beta-OHT, was found to be a minor metabolite formed by human liver microsomal enzymes. It was formed more readily by CYP3A4 than by either CYP2C9 or CYP2C19. 11beta-Hydroxylation was inhibited by ketoconazole (IC50 = 30 nM) at concentrations similar to the IC50 (36 nM) for 6beta-hydroxylation. Therefore, CYP3A4 could be mainly responsible for testosterone 11beta-hydroxylation in the human liver. These findings identify human hepatic biotransformation of testosterone to 11beta-OHT as a previously unrecognized extra-adrenal metabolic pathway.
Абстракты можно было кидать долго, но я далеко не фармаколог и не эндокринолог.
Мне бы хотелось получить мнение Галины Афанасьевны. Если кетоконазал и итраконазол являются конкурентными ингибиторами метаболизма тестостерона в печени, то может ли это привести к данным жалобам. Я естественно принимаю Вашу точку зрения, что этиология подобных состояний может широко варьировать.