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Journal of Clinical Endocrinology & Metabolism, Vol 65, 551-554, Copyright © 1987 by Endocrine Society


ARTICLES

Kinetic analysis of inhibition of human adrenal steroidogenesis by ketoconazole

RM Couch, J Muller, YS Perry and JS Winter

The kinetics of the inhibitory effects of the imidazole antimicrobial ketoconazole on the activities of the steroidogenic enzymes distal to cholesterol side-chain cleavage were studied in human adrenal microsomal and mitochondrial suspensions. Although ketoconazole was a competitive inhibitor of all five enzyme reactions, the effects on 17- hydroxylase, 17,20-desmolase, and 11-hydroxylase activities (Ki = 10(- 8) M) were considerably greater than those on 21-hydroxylase and 3 beta- hydroxysteroid dehydrogenase/isomerase activities (Ki = 10(-4) M). These findings explain the clinical endocrine effects of ketoconazole in the usual therapeutic doses, which include inhibition of cortisol and androgen secretion, compensatory ACTH-mediated secretion of 17- desoxysteroids such as progesterone and aldosterone, and suppression of PRA.


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