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Kinetic Analysis of Inhibition of Human Adrenal Steroidogenesis by Ketoconazole^*

Department of Pediatrics, University of Manitoba, and the Children's Hospital Winnipeg, Manitoba, Canada

Address requests for reprints to: Dr. J. S. D. Winter, Children's Hospital of Winnipeg, 840 Sherbrook Street, Winnipeg, Manitoba, R3A 1S1 Canada.

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 (K_i = 10^–8 M) were considerably greater than those on 21-hydroxylase and 3β-hydroxysteroid dehydrogenase/isomerase activities (K_i = 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.

^* This work was supported by grants from the Medical Research Council of Canada, the Children's Hospital of Winnipeg Research Foundation, the St. Boniface Hospital Research Foundation, and the Danish Medical Research Foundation.

Received January 21, 1987.

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