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Lack of antiviral activity of ketoconazole alone or in combination with the acyclic nucleoside ganciclovir against a herpes virus type 2 infection in mice.

Pecyk RA, Fraser-Smith EB, Matthews TR.

Syntex Research Palo Alto.

Ketoconazole and ganciclovir were tested for antiviral activity, each alone and in combination, against a herpes simplex virus type 2 (HSV-2) systemic infection in Swiss-Webster mice. When given once daily for 5 days starting 24 hr after infection, the ED50 for ketoconazole either alone or in combination was greater than 60 mg/kg; for ganciclovir, the ED50 was 7.1 mg/kg alone and 10.8 mg/kg in combination. Thus, ketoconazole did not potentiate or antagonize the antiviral activity of an acyclic nucleoside. Consequently, AIDS patients could perhaps receive ketoconazole and ganciclovir simultaneously for fungal and viral opportunistic infections without interference with their respective efficacies.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2576599&dopt=Abstract ketoconazole Nizoral



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Inhibition and induction of bile acid synthesis by ketoconazole. Effects on bile formation in the rat.

Kuipers F, Havinga R, Huijsmans CM, Vonk RJ, Princen HM.

Department of Pediatrics, University of Groningen, The Netherlands.

The effects of ketoconazole, an antimycotic agent, and metyrapone, an inhibitor of mixed function oxidases, on bile acid synthesis were compared in the rat both in vitro and in vivo. In rat liver microsomes, ketoconazole was much more potent than metyrapone in inhibiting the activity of cholesterol 7 alpha-hydroxylase, the rate-limiting enzyme in the synthesis of bile acids. The I50 values were 0.42 microM and 0.91 mM for ketoconazole and metyrapone, respectively. Intraduodenal administration of ketoconazole caused a rapid, dose-dependent reduction of bile acid synthesis in eight-day bile diverted rats. A single dose of 50 mg/kg reduced bile acid synthesis to 5% of control value; the same dose of metyrapone caused a reduction to only 85%. Inhibition of bile acid synthesis by ketoconazole was followed by a marked overshoot. At 28 hr after injection of 50 mg/kg of the drug, formation of bile acids was stimulated maximally by 45% compared to control value and remained elevated for more than 20 hr thereafter. Synthesis of all primary bile acids was affected to the same extent. Cholesterol 7 alpha-hydroxylase activity in livers of ketoconazole treated (30 mg/kg) rats with an intact enterohepatic circulation was increased by 70% at 16 hr after i.p. injection of the drug. During the very large decrease of biliary bile acid output with ketoconazole, bile flow rate was relatively increased, due to stimulation of the bile acid-independent fraction of bile flow. The latter effect can probably be explained as caused by biliary secretion of osmotically active metabolites of ketoconazole.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2586232&dopt=Abstract ketoconazole Nizoral



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Steroid-specific effects of ketoconazole on corticosteroid disposition: unaltered prednisolone elimination.

Ludwig EA, Slaughter RL, Savliwala M, Brass C, Jusko WJ.

Buffalo General Hospital, NY.

Ketoconazole inhibits the clearance of methylprednisolone by 60 percent and extends cortisol suppression beyond that produced by methylprednisolone alone. This study examined prednisolone pharmacokinetics and cortisol suppression in four healthy male volunteers following administration of prednisone 20 mg. Studies were performed with and without ketoconazole 200 mg po for six days. Blood samples were obtained serially over 24 hours and serum prednisone, prednisolone, and cortisol concentrations were determined by HPLC. Prednisolone clearance before and after ketoconazole therapy was not significantly different (160 +/- 38 vs. 148 +/- 23 mL/h/kg). In addition, no significant differences were found in mean residence time (5.03 +/- 0.69 vs. 6.18 +/- 1.77 h), terminal slope (0.23 +/- 0.03 vs. 0.19 +/- 0.05 h-1), or volume of distribution (0.79 +/- 0.11 vs. 0.84 +/- 0.12 L/kg). The ratio of cortisol area under the concentration versus time curve (AUC) 0-24 hours after prednisone administration to the AUC under baseline conditions was used as a measure of adrenal suppression. This ratio was not significantly different after prednisolone with and without ketoconazole (0.40 +/- 0.10 vs. 0.45 +/- 0.03). Renal excretion of prednisone and prednisolone was not significantly changed with ketoconazole. Based on this preliminary study, ketoconazole minimally alters prednisolone clearance in contrast to the significant ketoconazole-methylprednisolone interaction previously reported.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2596127&dopt=Abstract ketoconazole Nizoral



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Regulation of hepatic cholesterol biosynthesis. Effects of a cytochrome P-450 inhibitor on the formation and metabolism of oxygenated sterol products of lanosterol.

Iglesias J, Gibbons GF.

Metabolic Research Laboratory, Nuffield Department of Clinical Medicine, Radcliffe Infirmary, Oxford, U.K.

The involvement of oxygenated cholesterol precursors in the regulation of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase activity was studied by examining the effect of ketoconazole on the metabolism of mevalonic acid, lanosterol and the lanosterol metabolites, lanost-8-ene-3 beta,32-diol,3 beta-hydroxylanost-8-en-32-al and 4,4-dimethylcholesta-8,14-dien-3 beta-ol, in liver subcellular fractions and hepatocyte cultures. Inhibition of cholesterol synthesis from mevalonate by ketoconazole at concentrations up to 30 microM was due exclusively to a suppression of cytochrome P-450LDM (LDM = lanosterol demethylase) activity, resulting in a decreased rate of lanosterol 14 alpha-demethylation. No enzyme after the 14 alpha-demethylase step was affected. When [14C]mevalonate was the cholesterol precursor, inhibition of cytochrome P450LDM was accompanied by the accumulation of several labelled oxygenated sterols, quantitatively the most important of which was the C-32 aldehyde derivative of lanosterol. There was no accumulation of the 24,25-oxide derivative of lanosterol, nor of the C-32 alcohol. Under these conditions the activity of HMG-CoA reductase declined. The C-32 aldehyde accumulated to a far greater extent when lanost-8-ene-3 beta,32-diol rather than mevalonate was used as the cholesterol precursor in the presence of ketoconazole. With both precursors, this accumulation was reversed at higher concentrations of ketoconazole in liver subcellular fractions. A similar reversal was not observed in hepatocyte cultures.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2604729&dopt=Abstract ketoconazole Nizoral



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Synergistic effect of ketoconazole and antineoplastic agents on hormone-independent prostatic cancer cells.

Eichenberger T, Trachtenberg J, Chronis P, Keating A.

Division of Urology, Toronto General Hospital, Ontario.

Ketoconazole has been recently used in the primary treatment of patients with metastatic cancer of the prostate and is identified as a potent inhibitor of cytochrome P450-dependent adrenal and testicular androgen production. The drug has also shown activity in patients failing conventional hormonal manipulation. We subsequently showed that ketoconazole in vitro has a direct cytotoxic effect on human androgen-independent prostatic cancer cell lines. In order to better define the possible role of ketoconazole on hormone-independent prostatic cancer, we incubated the cells from human androgen-independent prostatic cancer lines in a methylcellulose tumour colony assay with different doses of the drug and increasing doses of conventional cytotoxic agents (etoposide, bleomycin, vinblastine, methotrexate, and teniposide). We demonstrated synergistic suppression of prostate cancer clonogenic cell growth by ketoconazole in the presence of vinblastine or etoposide. This observation may assign a new and important role for ketoconazole as part of combination chemotherapy in the treatment of patients with advanced prostatic cancer.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2612088&dopt=Abstract ketoconazole Nizoral



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Effect of ketoconazole and terbinafine on the pharmacokinetics of caffeine in healthy volunteers.

Wahllander A, Paumgartner G.

Department of Medicine II, University of Munich, Federal Republic of Germany.

The effects of single oral doses of ketoconazole 400 mg and terbinafine 500 mg on the hepatic microsomal system have been investigated in 8 healthy male volunteers. Microsomal activity caffeine was assessed by following the metabolism of 3 mg/kg bodyweight i.v. administered 1 h after the drug. The inhibitory effect of terbinafine was more pronounced than that of ketoconazole: clearance was decreased from 1.34 ml.kg-1.min-1 in controls to 1.06 and 1.21 ml.kg-1.min-1, respectively, and the corresponding half-life was increased from 5.8 h in controls to 7.6 and 6.7 h, respectively. The apparent volume of distribution remained unchanged. The serum levels of the antimycotics were within the therapeutic range in each subject. Although all three substances are metabolised by microsomes, the kinetic parameters (Cmax, half-life, elimination constant) of the antimycotics were poorly if at all correlated with the elimination of caffeine.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2612543&dopt=Abstract ketoconazole Nizoral



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Impact of ketoconazole on the metabolism of prednisolone.

Zurcher RM, Frey BM, Frey FJ.

Medizinische Poliklinik, University of Berne, Switzerland.

The impact of ketoconazole (200 mg for 7 days) on the kinetics of oral prednisone and intravenous prednisolone and on the apparent activity of the 6 beta-hydroxylase was investigated in 10 healthy volunteers. The ratio of urinary 6 beta-OH-cortisol/17-OH-corticosteroids declined by greater than 50% and the urinary excretion of 6 beta-OH-prednisolone decreased more than twofold in all subjects. The decline of the activity of the 6 beta-hydroxylase was associated with impaired metabolic and renal clearances of total and unbound prednisolone. The ratios of the AUCs of prednisolone/prednisone after oral prednisone and intravenous prednisolone were independent of the administration of ketoconazole, suggesting that the enzymes responsible for the interconversion of prednisolone in equilibrium prednisone were not affected by ketoconazole. Thus ketoconazole inhibits 6 beta-hydroxylase and increases the exposure of the body to the biologically active unbound prednisolone after oral prednisone or intravenous prednisolone.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2639662&dopt=Abstract ketoconazole Nizoral