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The influence of ketoconazole on human adrenal steroidogenesis: incubation studies with tissue slices.

Engelhardt D, Weber MM, Miksch T, Abedinpour F, Jaspers C.

Medical Department II, Klinikum Grosshadern, University of Munich, FR Germany.

OBJECTIVE: The influence of ketoconazole on the various enzymes of human adrenal steroid biosynthesis was examined in vitro. MEASUREMENTS: After incubation of human adrenal tissue slices with labelled precursors and ketoconazole (0-2000 microM), radioactive metabolites were separated by thin-layer chromatography and quantified by liquid scintillation counting. Enzyme activity was assessed by measuring conversion of tritium-labelled precursors to products. RESULTS: In vitro, ketoconazole showed a significant inhibition on the following adrenal enzyme systems (with decreasing activity): C17,20-desmolase (IC50 2 microM), 16 alpha-hydroxylase (IC50 9 microM), 17 alpha-hydroxylase (IC50 18 microM), 18-hydroxylase (IC50 28 microM), and 11 beta-hydroxylase (IC50 35 microM). In the tested concentrations ketoconazole had no inhibitory effect on the 21-hydroxylase, the 3 beta-hydroxysteroid dehydrogenase and the 20-hydroxysteroid dehydrogenase component of the C17,20-desmolase enzyme system. CONCLUSIONS: The data are in accordance with clinical findings where a strong suppression of serum androgen levels by relatively selective inhibition of C17, 20-desmolase has been assumed. The predominant blocking effect of ketoconazole on adrenal as well as on gonadal androgen biosynthesis might be of clinical benefit in the management of hyperandrogenic states.

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Bioavailability of fluconazole and ketoconazole in human stratum corneum and oral mucosa.

Pierard GE, Rurangirwa A, Pierard-Franchimont C.

Department of Dermatopathology, University of Liege, Belgium.

In this study, the bioavailability of fluconazole and ketoconazole in the stratum corneum and oral mucosa after multiple oral dosages were compared. It is well recognized that such evaluation is heavily dependent on the test methods employed. A method of culture of fungi on human stratum corneum and superficial mucosal cells, a model close to the in-vivo situation, was used. A significant difference in the bioavailability of the two antifungals in stratum corneum and superficial cells of oral mucosa was found. The activity of ketoconazole proved to be more rapid against T. mentagrophytes while fluconazole appeared slightly more active against C. albicans.

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Effect of ketoconazole on methylprednisolone pharmacokinetics and receptor/gene-mediated pharmacodynamics.

Haughey DB, Jusko WJ.

Department of Pharmaceutics, School of Pharmacy, State University of New York, Buffalo.

The disposition of methylprednisolone (MPL) and its metabolite, methylprednisone, and the receptor/gene-mediated pharmacodynamics of methylprednisolone were examined in control and ketoconazole-treated rats. Oral doses of ketoconazole (50 mg/kg/day) for 3 days increased plasma MPL clearance by 50% (NS) with no change in volumes of distribution. The mean residence time decreased from 0.60 +/- 0.15 (control) to 0.43 +/- 0.10 hr with ketoconazole (P less than .05) after 5 mg/kg of MPL (free alcohol). The methylprednisone to MPL area under the curve ratio decreased from 0.19 +/- 0.04 in control to 0.14 +/- 0.03 in ketoconazole-treated rats (P less than .05) due to altered interconversion between these steroids. An improved pharmacokinetic/dynamic receptor/gene-mediated model characterized the steroid receptor binding and induction of tyrosine aminotransferase activity after i.v. MPL sodium succinate (10 mg/kg). In contrast to previous in vitro studies, ketoconazole at maximally tolerated doses failed to antagonize the steroid receptor-mediated activity of MPL. Although ketoconazole at high concentrations competitively inhibited the in vitro binding of steroid to hepatic receptors, no in vivo inhibition was detected after large p.o. ketoconazole doses. Efficiency of tyrosine aminotransferase induction was slightly enhanced in ketoconazole animals. Pharmacokinetic/dynamic factors accounting for the lack of antiglucocorticoid activity primarily include the low ketoconazole receptor binding affinity.

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Effects of pentamidine alone and in combination with ketoconazole or itraconazole on the growth of Candida albicans.

St-Germain G.

Laboratoire de Sante Publique du Quebec, Sainte-Anne-de-Bellevue, Canada.

The in vitro interaction of pentamidine with ketoconazole and with itraconazole was studied with 10 strains of Candida albicans isolated from acquired immunodeficiency syndrome patients and one azole-resistant strain. Although growth curves indicated that concentrations of 1 microgram or more of pentamidine per ml significantly inhibited the growth of C. albicans, MICs and minimum fungicidal concentrations (MFCs) were greater than or equal to 10 micrograms/ml. Combinations of ketoconazole and pentamidine did not appear to have any significant effect on MICs or MFCs with most strains. However, the azole-resistant strain exhibited a 2-log decrease in MIC when exposed to ketoconazole combined with 1.0 microgram or more of pentamidine per ml. Similar results were obtained with itraconazole. An Eagle, or paradoxical, effect was observed with four strains exposed to itraconazole alone and in combination with 0.01 and 0.1 microgram of pentamidine per ml. This effect was not seen when concentrations of pentamidine reached 1.0 microgram/ml. Although no fungicidal effect was observed with any of these drugs alone, itraconazole combined with 10 micrograms of pentamidine per ml was fungicidal for eight strains. No signs of antagonism between pentamidine and these two antifungal agents were observed.

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Effects of the antifungal imidazole ketoconazole on CYP1A and CYP3A in rainbow trout and killifish.

Hegelund T, Ottosson K, Radinger M, Tomberg P, Celander MC.

Goteborg University, Department of Zoophysiology, Box 463, SE 405 30 Goteborg, Sweden.

The use of N-substituted imidazoles is widespread, and imidazole and triazole fungicides have been detected in the aquatic environment and shown to bioaccumulate in fish. We have investigated effects of the model imidazole, ketoconazole, on drug-metabolizing cytochrome P450 (CYP) forms. We focused on cytochrome P4501A (CYP1A) and cytochrome P4503A (CYP3A) expression and activities in juvenile rainbow trout and in adult killifish. The CYP1A expression (mRNA, protein) and activity was induced in rainbow trout, whereas in killifish no effect of ketoconazole on CYP1A protein expression was observed. A biphasic dose-response relationship was observed between ketoconazole exposure and hepatic CYP1A-mediated ethoxyresorufin O-deethylase (EROD) activity in rainbow trout in vitro and in vivo, implying that higher doses of ketoconazole inhibit CYP1A activities. Slight induction of CYP3A protein levels was observed in rainbow trout exposed in vivo to ketoconazole. However, the CYP3A-mediated benzyloxy-4-[trifluoromethyl]-coumarin (BFC) O-debenzyloxylase activity was reduced in rainbow trout and killifish treated with ketoconazole. In vitro inhibition studies confirmed that ketoconazole was a potent inhibitor of both CYP3A and CYP1A enzyme activities in these species. This study showed that ketoconazole induced CYP1A and CYP3A expression in rainbow trout. However, the most pronounced effect of ketoconazole was a 60 to 90% decrease in CYP3A catalytic activities in rainbow trout and in killifish.

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Progesterone metabolism in hepatic microsomes. Effect of the cytochrome P-450 inhibitor, ketoconazole, and the NADPH 5 alpha-reductase inhibitor, 4-MA, upon the metabolic profile in human, monkey, dog, and rat.

Swinney DC.

Department of Drug Metabolism, Syntex Research, Palo Alto, CA 94304.

Progesterone was incubated in the presence of NADPH with hepatic microsomes isolated from male and female human, monkey, dog, and rat and the effect of 17 beta-NN-diethylcarbamoyl-4-methyl-4-aza-5 alpha- androstan-3-one (4-MA), an NADPH 5 alpha-reductase inhibitor, and ketoconazole, a cytochrome P-450 inhibitor, upon oxidative metabolism was evaluated. 4-MA caused an increase in detectable oxidative products only with microsomes isolated from rat. An increase in 2 alpha- and 16 alpha-hydroxylation was observed in male rat, and an increase in the formation rate of nine products was observed in female rat. delta 6-Progesterone, 6 beta-, 15 alpha-, 16 alpha-, and 21-hydroxyprogesterone (6 beta-, 15 alpha-, 16 alpha-, and 21-OHP) were common products in both sexes of all species studied. Differences were observed in the formation rate of 2 alpha-, 2 beta-, 6 alpha-, 7 alpha-, and 17 alpha-OHPs. At the 2-carbon, microsomes isolated from both sexes of primates hydroxylated progesterone exclusively at the 2 beta-position. Microsomes from both dog sexes and female rat formed 2 alpha- and 2 beta-OHP, while microsomes isolated from male rat formed exclusively 2 alpha-OHP. 7 alpha-Hydroxylation was detected exclusively in rat, and 6 alpha-hydroxylation was detected in both dog and rat. 17 alpha-Hydroxylase activity in primates was detected only in microsomes from male human. IC50 values associated with ketoconazole inhibition of progesterone metabolism differed among species.(ABSTRACT TRUNCATED AT 250 WORDS)

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Hypolipidemic effect and mechanism of ketoconazole without and with cholestyramine in familial hypercholesterolemia.

Gylling H, Vanhanen H, Miettinen TA.

Second Department of Medicine, University of Helsinki, Finland.

The hypocholesterolemic and metabolic effects of ketoconazole (400 mg/d) alone (inhibits cholesterol synthesis at 14 alpha-demethylation of lanosterol) and in combination with cholestyramine (12 g/d), were studied in nine women with xanthomatous familial hypercholesterolemia (FH). In addition to serum lipoprotein levels, cholesterol precursors, fecal steroids, and cholesterol absorption were measured before and during the drug treatments. Serum total and low-density lipoprotein (LDL)-cholesterol were reduced by 19% and 22% with ketoconazole; the respective changes were 16% and 21% for cholestyramine, and 31% and 41% for the combined ketoconazole and cholestyramine treatment. Serum triglycerides, very-low-density lipoprotein (VLDL)-and high-density lipoprotein (HDL)-cholesterol levels were unchanged. Accumulation of cholesterol precursors in serum suggested that ketoconazole inhibited cholesterol synthesis at delta 8-sterol levels. Serum and fecal lanosterols were increased up to 20-fold and were interrelated. Their maximal serum level was 1.3 mg/DL and the lanosterol contents were negatively related to the serum cholesterol levels. The intestinal absorption and total intestinal fluxes of cholesterol were reduced by 27% and 29%. Cholesterol and bile acid synthesis were decreased by ketoconazole only when combined with cholestyramine. The synthesis of chenodeoxycholic acid was deeply hindered by ketoconazole. Thus, ketoconazole efficiently lowers serum total and LDL-cholesterol levels in FH patients, probably by inhibiting cholesterol synthesis and absorption. Effective biliary and fecal outputs of cholesterol precursors prevent their excessive increase in serum.(ABSTRACT TRUNCATED AT 250 WORDS)

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1984567&dopt=Abstract ketoconazole Nizoral