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THE IN VITRO METABOLISM OF DIGITOXIGENIN.
Abstract
The number of hydroxyl groups on the steroid nucleus of cardiac glyco- sides can influence the absorption, disposition, susceptibility to metabolism, and excretion of cardio-active steroids. In this study, the cardenolide, digitoxigenin, was employed as a model substrate to investigate the hydroxyla- tion of the steroid nucleus of cardiac glycosides. The major portion of this investigation employed rabbit liver homogenates. However, guinea pig liver homogenates and rat liver, adrenal, and ovary preparations were also used.3H-Digitoxigenin was metabolized in vitro by rabbit liver homogenate in the presence of an NADPH generating system. Two polar metabolites resulting from this biotransformation were isolated and identified as 68-hydroxy-3-epi- digitoxigenin, the major metabolite, and 56-hydroxydigitoxigenin (periplogenin). The previously identified 3-dehydrodigitoxigenin and 3-epidigitoxigenin were also present as metabolites. This is the first demonstration of the C-5 hydroxy- lation of digitoxigenin by a mammalian system. The major metabolite represents the first conformation of the hydroxylation of digitoxigenin at C-6. The forma- tion of this metabolite can be increased by phenobarbital pretreatment. Pre- treatment with phenobarbital also enhanced aniline metabolism and the cytochrome P-450 content of rabbit liver microsomes, The sequence in the biosynthesis of the major metabolite appears to be: digitoxigenin, 3-dehydrodigitoxigenin, 3- epidigitoxigenin, 68-hydroxy-3-epidigitoxigenin, whereas 58-hydroxydigitoxigenin is formed directly from digitoxigenin. No 128-hydroxydigitoxigenin was isolated.
Subject Area
Pharmacology
Recommended Citation
BULGER, WILLIAM HARVEY, "THE IN VITRO METABOLISM OF DIGITOXIGENIN." (1974). ETD collection for University of Nebraska-Lincoln. AAI7503411.
https://digitalcommons.unl.edu/dissertations/AAI7503411