• Proceedings of the Korean Society of Toxicology Conference
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• 2003.05a
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• pp.95.2-95
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• 2003

Ketoconazole is a well-studied drug that blocks fungal growth and testosterone synthesis in humans and rodents by inhibiting the activity of cytochrome P-450 enzymes. But there were no reports that ketoconazole affects on enzymes related to degradation of testosterone. Aromatase converts testosterone to estradiol. Change of aromatase protein level may destroy hormone homeostasis. (omitted)

• Archives of Pharmacal Research
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• v.22 no.3
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• pp.255-261
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• 1999

The effect of biphenyl dimethyl dicarboxylate (PMC) on the cellular and nonspecific immunosuppressions by ketoconazole (KCZ) was investigated in ICR mice. PMC at a dose of 6 mg/kg was administered orally to mice daily for 14 consecutive days. KCZ was suspended in RPMI 1640 medium and orally administered at 160 mg/kg/day 2 hrs after the administration of PMC. Immune responses of the delayed-type hypersensitively (DTH) reaction to sheep red blood cells (SRBC), phagocytic activity and natural killer (NK) cell activity were evaluated. DTH reaction to SRBC was enhanced to normal level by the combination of PMC and KCZ, as compared with treatment of KCZ alone. In the combination of PMC and KCZ, as compared with treatment of KCZ alone, there were also significant increases in activities of natural killer (NK) cells and phagocytes along with circulating leukocytes. These findings indicate that PMC shows a significant restoration from the immunotoixc status induced by KCZ.

• Journal of Yeungnam Medical Science
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• v.9 no.2
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• pp.396-406
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• 1992

Various susceptibility tests have been used to determine minimal inhibition concentration(MIC) of dermatophytes. They have limitations to apply practically because they need long time to determine MIC. Authors examined MIC of T. rubrum to ketoconazole and itraconazole using 96-well microplate and 24-well macroplate by method of Granade and Artis and tried to check the possibility of this method on clinical application. Nine strains of T. rubrum from patients with dermatophytosis were used. Evaluations of the factors affecting MIC were also tried. The results were as follows. 1. Effect of inoculation density on determination time and MIC : Determination of MIC were possible in 4th days after inoculation at higher inoculation density Caborbance 2.0, 1.0) compared to 6th days at lower inoculation density(absorbance 0.5, 0.25). 2. Effect of incubation temperature on MIC : When incubating at $37^{\circ}C$, MIC were below 0.006-$0.04{\mu}g/ml$ to ketokckonazole and below 0.006-$0.04{\mu}g/ml$ to itraconazole while at $25^{\circ}C$ 0.08-$5.68{\mu}g/ml$ to ketoconazole and 0.006-$0.71{\mu}g/ml$ to itraconazole. Significant reduction of MIC was observed at $37^{\circ}C$ compared to $25^{\circ}C$. 3. Effect of container size on determination time and MIC : When incubating in 96-well microplate and 24-well macroplate, determination of MIC was possible in 4th to 6th days after inoculation in broth-containig 96-well microplate compared to 8th to 12th days in broth-containing 24-well macroplate. But no difference in MIC was observed between different container size. 4. Effect of media on MIC : When using broth as media, MIC were below 0.006-$5.68{\mu}g/ml$ to ketoconazole, below 0.006-$0.36{\mu}g/ml$ to itraconazole in broth-containg 24-well macroplate. When using agar as media, MIC were below 0.006-$5.68{\mu}g/ml$ to ketoconzole, below 0.006-$5.68{\mu}g/ml$ to intraconzole in agar-containing 24-well macroplate. There was slight increase of MIC with agar media compared to broth media. 5. These findings confirm that determination of MIC of dermatophtes by method of Granade and Artis is fast and simple technique for antifungal susceptibility test.

• Journal of Pharmaceutical Investigation
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• v.24 no.2
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• pp.95-104
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• 1994

Inclusion complexes of ketoconazole(KT) with ${\alpha}^_$, ${\beta}^_$cyclodextrin(CD) and $dimethy1-{\beta}-cyclodextrin$ (CD) and $dimethy1-{\beta}-cyclodextrin(DM{\beta}CD)$ as nasal absorption enhancer were prepared in 1: 2 molar ratios by freeze-drying and solvent evaporation methods. In order to compare with the intrinsic absorptivity of KT in the jejunum(J) and the nasal cavity(N), the in situ simultaneous perfusion method was employed. The in situ recirculation study revealed that KT-CD inclusion complexes with the greater stability constant and the faster dissolution rate proportionally increased the absorption of KT in the J and N of rats. The rank order of apparent KT permeability$(P_{app}\;:\;cm/sec\;{\time}\;1O^{-5}{\pm}S.E.)$, corrected by surface area of absorption, was $5.10{\pm}0.3(N,\; KT-DM{\beta}CD)$ )> $4.13{\pm}0.4(N,\;KT-{\beta}-CD)$ )> $3.52{\pm}0.2(N,\;KT-{\alpha}-CD)$ )> $2.76{\pm}0.3(J,\; KT-DM{\beta}CD)$ )> $2.61{\pm}0.5(J,\;KT-{\beta}-CD)$ )> $2.42{\pm}0.4(J,\;KT-{\alpha}-CD)$ at pH 4.0. The in crease in permeability of $KT-DM{\beta}CD$ inclusion complex was 2.6 folds in the J and 4.5 folds in the N when the perfusing solution was changed from the buffer(pH 4.0) to saline. The absorption rate of $KT-DM{\beta}CD$ inclusion complex after nasal administration was more rapid than those of ketoconazole alone and $KT-DM{\beta}CD$ inclusion complex after oral administration to rats. In comparision with an oral administration of ketoconazole suspension in corn oil, the relative bioavailability was calculated 137.3% for the oral and 195.0% for nasal $KT-DM{\beta}CD$ inclusion complex in rats. The present results suggest that $KT-DM{\beta}CD$ inclusion complex may serve as a potential nasal absorption enhancer for the nasal delivery of ketoconazole.

• Korean Journal of Clinical Pharmacy
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• v.26 no.4
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• pp.312-317
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• 2016

Objective: Midazolam is mainly metabolized by cytochrome P450 (CYP) 3A. Inhibition or induction of CYP3A can affect the pharmacological activity of midazolam. The aims of this study were to develop a population pharmacokinetic (PK) model and evaluate the effect of CYP3A-mediated interactions among ketoconazole, rifampicin, and midazolam. Methods: Three-treatment, three-period, crossover study was conducted in 24 healthy male subjects. Each subject received 1 mg midazolam (control), 1 mg midazolam after pretreatment with 400 mg ketoconazole once daily for 4 days (CYP3A inhibition phase), and 2.5 mg midazolam after pretreatment with 600 mg rifampicin once daily for 10 days (CYP3A induction phase). The population PK analysis was performed using a nonlinear mixed effect model ($NONMEM^{(R)}$ 7.2) based on plasma midazolam concentrations. The PK model was developed, and the first-order conditional estimation with interaction was applied for the model run. A three-compartment model with first-order elimination described the PK. The influence of ketoconazole and rifampicin, CYP3A5 genotype, and demographic characteristics on PK parameters was examined. Goodness-of-fit (GOF) diagnostics and visual predictive checks, as well as bootstrap were used to evaluate the adequacy of the model fit and predictions. Results: Twenty-four subjects contributed to 900 midazolam concentrations. The final parameter estimates (% relative standard error, RSE) were as follows; clearance (CL), 31.8 L/h (6.0%); inter-compartmental clearance (Q) 2, 36.4 L/h (9.7%); Q3, 7.37 L/h (12.0%), volume of distribution (V) 1, 70.7 L (3.6%), V2, 32.9 L (8.8%); and V3, 44.4 L (6.7%). The midazolam CL decreased and increased to 32.5 and 199.9% in the inhibition and induction phases, respectively, compared to that in control phase. Conclusion: A PK model for midazolam co-treatment with ketoconazole and rifampicin was developed using data of healthy volunteers, and the subject's CYP3A status influenced the midazolam PK parameters. Therefore, a population PK model with enzyme-mediated drug interactions may be useful for quantitatively predicting PK alterations.

• Journal of the Society of Cosmetic Scientists of Korea
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• v.25 no.4 s.34
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• pp.1-5
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• 1999

The purpose of this study was to determine the effect of IPBC(3-lodo-2-propynylbutylcarbamate) on dandruff caused by the anthropophilic fungus Malassezia furfur. The effects of IPBC on dandruff were examined by evaluating (a) the MIC value of IPBC using broth dilution method; (b) the remnant antimicrobial activity of IPBC containing shampoo on skin disc; (c) the antidandruff efficacy of 1.0 % IPBC containing shampoo in double blind clinical trial. To investigate the remnant antimicrobial activity of IPBC against Malassezia furfur, guinea pig-skin disc was washed with antidandruff shampoo and then the diameter of inhibition zone per disc was measured. For clinical trial, thirty healthy volunteers, aged 25-35, participated in 4 week study. At 0, 2, 4 weeks, examinations of scaling, itching on scalp were carried out. The MIC(Minimun Inhibition Concentration) values of IPBC range from 0.10 to 1.00${\mu}g/ml$ and it seems that IPBC is more effective in the MIC values than zinc pyrithione, selenium disulphide, piroctone olamine and comparable to ketoconazole, climbazole. When the remnant antimicrobial activity of IPBC shampoo on skin disc was determined, 0.5% IPBC shampoo and 2.0% Ketoconazole shampoo resulted in similar antimicrobial effect. In addition, 1.0%, 2.0% IPBC shampoo was more effective than 2.0% ketoconazole shampoo. After two and four-weeks of 1.0% IPBC shampoo treatment, there was significant reduction of scaling, itching in test group compared to control group. On the basis of these results, it can be concluded that 1.0% IPBC is more effective than 2.0% Ketoconazole in reducing dandruff. It seems that strong capacity of drug binding to the stratum corneum plays a role in its antidandruff effect since adsorption of active ingredients on scalp is very important factor in reducing dandruff.

• Biomolecules & Therapeutics
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• v.26 no.5
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• pp.494-502
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• 2018

Breast cancer is currently the most prevalent cancer in women, and its incidence increases every year. Azole antifungal drugs were recently found to have antitumor efficacy in several cancer types. They contain an imidazole (clotrimazole and ketoconazole) or a triazole (fluconazole and itraconazole) ring. Using human breast adenocarcinoma cells (MCF-7 and MDA-MB-231), we evaluated the effects of azole drugs on cell proliferation, apoptosis, cell cycle, migration, and invasion, and investigated the underlying mechanisms. Clotrimazole and ketoconazole inhibited the proliferation of both cell lines while fluconazole and itraconazole did not. In addition, clotrimazole and ketoconazole inhibited the motility of MDA-MB-231 cells and induced $G_1$-phase arrest in MCF-7 and MDA-MB-231 cells, as determined by cell cycle analysis and immunoblot data. Moreover, Transwell invasion and gelatin zymography assays revealed that clotrimazole and ketoconazole suppressed invasiveness through the inhibition of matrix metalloproteinase 9 in MDA-MB-231 cells, although no significant changes in invasiveness were observed in MCF-7 cells. There were no significant changes in any of the observed parameters with fluconazole or itraconazole treatment in either breast cancer cell line. Taken together, imidazole antifungal drugs showed strong antitumor activity in breast cancer cells through induction of apoptosis and $G_1$ arrest in both MCF-7 and MDA-MB-231 cells and suppression of invasiveness via matrix metalloproteinase 9 inhibition in MDA-MB-231 cells. Imidazole drugs have well-established pharmacokinetic profiles and known toxicity, which can make these generic drugs strong candidates for repositioning as antitumor therapies.

• Proceedings of the SCSK Conference
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• 1999.10a
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• pp.1-5
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• 1999

The purpose of this study was to determine the effect of IPBC(3-lodo-2-propynylbutyl carbamate) on dandruff caused by the anthropophilic fungus Maiassezia furfur. The effects of IPBC on dandruff were examined by evaluating (a) the MIC value of IPBC using broth dilution method : (b) the remnant antimicrobial activity of IPBC containing shampoo on skin disc ; (c) the antidandruff efficacy of 1.0 % IPBC containing shampoo in double blind clinical trial. To investigate the remnant antimicrobial activity of IPBC against Maiassezia furfur, guinea pig-skin disc was washed with antidandruff shampoo and then the diameter of inhibition zone per disc was measured. For clinical trial, thirty healthy volunteers, aged 25-35, participated in 4 week study. At 0,2,4 weeks, examinations of scaling, itching on scalp were carried out. The MIC(Minimun Inhibition Concentration) values of IPBC range from 0.10 to 1.00$\mu$ g/ml and it seems that IPBC is more effective in the MIC values than zinc pyrithione, selenium disulphide, piroctone olamine and comparable to ketoconazole, climbazole. When the rimnant antimicrobial activity of IPBC shampoo on skin disc was determined, 0.5% IPBC shampoo and 2.0% Ketoconazole shampoo resulted in similar antimicrobial effect. In addition, 1.0%,2.0% IPBC shampoo was more effective than 2.0% ketoconazole shampoo. After two and four-weeks of 1.0% IPBC shampoo treatment, there was significant reduction of scaling, itching in test group compared to control group. On the basis of these results, it can be concluded that 1.0% IPBC is more effective than 2.0% Ketoconazole in reducing dandruff. It seems that strong capacity of drug binding to the stratum corneum plays a role in its antidandruff effect since adsorption of active ingredients on scalp is very important factor in reducing dandruff.

• Journal of Applied Biological Chemistry
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• v.56 no.2
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• pp.109-112
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• 2013

Azole fungicides are one of the most wide-spread antifungal compounds in agriculture and pharmaceutical applications. Their major mode of action is the inhibition of ergosterol biosynthesis, giving depletion of ergosterol, precursors and abnormal steroids. However, metabolic consequences of such inhibition, other than steroidal metabolitesare not well established. Comprehensive metabolic profiles of Saccharomyces cerevisiae has been presented in this study. Wild type yeast was treated either with glucose as control or azole fungicide (ketoconazole). Both polar metabolites and lipids were analyzed with gas chromatography-mass spectrometry. Approximately over 180 metabolites were characterized, among which 18 of them were accumulated or depleted by fungicide treatment. Steroid profile gives the most prominent differences, including the accumulation of lanosterol and the depletion of zymosterol and ergosterol. However, the polar metabolite profile was also highly different in pesticide treatment. The concentration of proline and its precursors, glutamate and ornithine were markedly reduced by ketoconazole. Lysine and glycine level was also decreased while the concentrations of serine and homoserine were increased. The overall metabolic profile indicates that azole fungicide treatment induces the depletion of many polar metabolites, which are important in stress response.

• Journal of Food Hygiene and Safety
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• v.11 no.4
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• pp.299-306
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• 1996

6-[(N-3,4-Dibromophenyl)amino]-7-chloro-5,8-quinolinedione(FCK13) was tested for antifungal activities. The MIC values were determined by the two-fold dilution method. The therapeutic potential of RCK13 had been assessed in comparison with ketoconazole and fluconazole against systemic infections with candida albicans in normal mice. RCK13 had ED50,0.80$\pm$0.21 mg/kg but ketoconazole had ED50, 8.00$\pm$0.73 mg/kg respectively. And administered RCK13 at the ED50 for 14 days improved survival rates as well as ketoconazole. Acute oral toxicity studies of RCK13 were carried out in ICR mice of both sexes. These acute oral toxicities of RCK13 were low and LD50 values were over 2,850 mg/kg in ICR mice. The genotoxicities of RCK13 had been evaluated. RCK13 was negative in Ames test with Salmonella typhimurium and chromosomal aberration test in CHL cells. The clastogenicity was tested on the RCK13 with in vivo mouse micronucleus assay. RCK13 did not show any clastogenic effect in mouse peripheral blood and was negative in mouse micronucleus assay. These results indicate that RCK13 has no genotoxic potential under these experimental conditions.