Nizoral
Blockade of HERG and Kv1.5 by ketoconazole.

Dumaine R, Roy ML, Brown AM.

Rammelkamp Center for Research, MetroHealth Medical Center, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.

Ketoconazole, a widely used fungicide in patients, has been associated with Q-T prolongation and torsade de pointes when co-administered with terfenadine (Seldane). Both compounds use the same cytochrome-P450 metabolic pathway, resulting in an increase in plasma concentration of terfenadine. We previously showed that terfenadine blocked HERG (Human Ether-a-Gogo Related Gene), an important component of the repolarizing cardiac delayed rectifier IK with concentration needed to obtain 50% of the block (IC50) in the therapeutic range (300 nM). Another target is Kv1.5 (delayed outward rectifier potassium current), an important component of human atrial ultrarapid delayed rectifier current. Whether Kv1.5 and HERG proteins are direct targets for ketoconazole has yet to be addressed. We heterologously expressed HERG and Kv1.5 in Xenopus oocytes and compared their sensitivities to ketoconazole. HERG and Kv1.5 currents were reduced comparably with apparent IC50 values of 49 microM and 107 microM, respectively, when measured using the two-microelectrode recording technique. The differences in the IC50 may help explain the preferential ventricular origin of the ketoconazole-associated arrhythmias during overdose. The mechanism of block was different between Kv1.5 and HERG. Cumulative application of terfenadine and ketoconazole at their respective IC50 concentrations resulted in current reductions that suggest an additive rather than a competitive type of block by the two drugs. We conclude that ketoconazole may potentiate the effects of terfenadine first by an indirect pharmacokinetic action to elevate plasma levels and second by a direct pharmacodynamic action on HERG currents. These potential dual actions on HERG currents suggest that precautions should be taken in long-term ketoconazole treatment, particularly for patients who have decreased liver function or are on a drug regimen requiring simultaneous medications that use cytochrome-P450 for breakdown, such as terfenadine or erythromycin, or Class III antiarrhythmic drugs.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9694927&dopt=Abstract ketoconazole Nizoral



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Effect of metabolic inhibitors on cyclosporine pharmacokinetics using a population approach.

McLachlan AJ, Tett SE.

Department of Clinical Pharmacology and Toxicology, St. Vincent's Hospital, Darlinghurst, Australia.

Drugs known to inhibit the metabolism of cyclosporine are administered concomitantly to those who undergo cardiothoracic transplantation. The aim of this study was to examine in quantitative terms the relationship between cyclosporine oral dose rate and the trough concentration (Css(trough)) at steady state in patients who undergo cardiothoracic transplantation and are administered cyclosporine alone or in combination with drugs known to inhibit its metabolism. Dose and whole blood cyclosporine Css(trough) observations measured using the enzyme-multiplied immunoassay technique (EMIT) (396 observations) or the TDx assay (435 observations) were collected as part of routine blood concentration monitoring from 182 patients who underwent cardiothoracic transplantation. Data were analyzed using a linear mixed-effects modeling approach to examine the effect of metabolic inhibitors on dose-rate-Css(trough) ratio. The mean (and 95% confidence interval) dose-rate-Css(trough) ratio for cyclosporine generated from concentrations measured using EMIT was 94 (82.5-105.5) Lh(-1) for patients administered cyclosporine alone, 66.7 (58.1-75.3) Lh(-1) for patients administered concomitant diltiazem, 47.9 (15.4 -80.4) Lh(-1) for patients administered concomitant itraconazole, 21.7 (14.8-28.5) Lh(-1) for patients administered concomitant ketoconazole, and 14.9 (11.8-18.1) Lh(-1) for patients concomitantly administered diltiazem and ketoconazole. For patients administered concomitant cyclosporine, ketoconazole, and diltiazem, the dosage of cyclosporine, if it is administered alone, should be 20% to achieve the same blood concentrations. This will allow safer drug concentration targeting of cyclosporine after cardiothoracic transplantation.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9712463&dopt=Abstract ketoconazole Nizoral



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In vitro susceptibility of filamentous fungi to itraconazole.

Venugopal PV, Venugopal TV.

Institute of Microbiology, Madurai Medical College, Madras, India.

The in vitro activity of itraconazole was investigated against 25 clinical isolates of filamentous fungi by agar dilution method. The isolated included Aspergillus sp., hyalohypomycetes, dematiaceous fungi and zygomycetes. Intraconazole was more active, inhibiting 50% (MIC 50) and 90% (MIC 90) of the Aspergillus sp., at a concentration of 0.5 and 2.5 ug ml-1 (MIC range 0.1 and 5 micrograms ml-1) Ketoconazole (MIC range 0.5-10 ug ml-1) required 1 and 5 ug ml-1 for inhibiting 50% and 90% of the isolates. For the hyalophypomycetes and dematiaceous fungi, the MIC 50s for itraconazole were 1 and 0.5 ug ml-1 and Ketoconazole required 2.5 ug ml-1 for both the groups. For the zygomycetes, the MIC range and MIC 50s for Ketoconazole were 1-100 and 10 ug ml-1 whereas the values for itraconazole were 5- > 100 and > 100 micrograms ml-1.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9726141&dopt=Abstract ketoconazole Nizoral



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Disk diffusion susceptibility testing of dermatophytes with imidazoles.

Venugopal PV, Venugopal TV.

Institute of Microbiology, Madurai Medical College.

In vitro susceptibility testing of 43 isolates of dermatophytes was carried out against imidazoles-ketoconazole, miconazole and econazole and griseofulvin by agar dilution and disk diffusion methods. Econazole was the most effective drug inhibiting all the isolates at a concentration of 0.1 microgram ml-1. The MIC 50s and MIC 90s for ketoconazole and miconazole were 1 and 2.5 mg ml-1 whereas the values for griseofulvin were 1 and 5 micrograms ml-1. Good correlation was seen between the MIC and sizes of zones of inhibition around the disks. Regression analysis was used to measure the degree of correlation between the MIC values and matched averaged zones of inhibition and the correlation coefficients for econazole, ketoconazole, miconazole and griseofulvin were -0.5554, -0.5886, -0.8558 and -0.8268 (p < 0.001) respectively.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9726146&dopt=Abstract ketoconazole Nizoral



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Voriconazole against fluconazole-susceptible and resistant candida isolates: in-vitro efficacy compared with that of itraconazole and ketoconazole.

Nguyen MH, Yu CY.

Department of Medicine, University of Florida College of Medicine, Gainesville 32610, USA. nguyemt medicine.ufl.edu

We compared the in-vitro activity of fluconazole, itraconazole, ketoconazole and voriconazole against 67 blood isolates of Candida spp. exhibiting a wide range of fluconazole MICs (0.125 to >64 mg/L). Voriconazole was the most potent in vitro, followed by itraconazole, ketoconazole and fluconazole. Itraconazole and voriconazole had in-vitro activity against fluconazole-susceptible and -resistant candida isolates. Higher itraconazole and voriconazole MICs were observed in isolates exhibiting higher fluconazole MICs, suggesting cross-resistance. Itraconazole and voriconazole MICs of > or =16 mg/L were observed only in Candida albicans and Candida tropicalis. Candida krusei and Candida glabrata exhibited itraconazole MICs of 0.5-1 mg/L and voriconazole MICs of 0.25-0.5 mg/L.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9738846&dopt=Abstract ketoconazole Nizoral



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Effects of ketoconazole on the intestinal metabolism, transport and oral bioavailability of K02, a novel vinylsulfone peptidomimetic cysteine protease inhibitor and a P450 3A, P-glycoprotein dual substrate, in male Sprague-Dawley rats.

Zhang Y, Hsieh Y, Izumi T, Lin ET, Benet LZ.

Department of Biopharmaceutical Sciences, School of Pharmacy, University of California, San Francisco, California, USA.

We investigated the effects of ketoconazole on the oral bioavailability of morpholine-urea-phenylalanine-homophenylalanine-vinylsulfone-phenyl (K02), a vinylsulfone peptidomimetic cysteine protease inhibitor, and a P450 3A (CYP3A) and P-glycoprotein dual substrate, in male Sprague-Dawley rats, so as to evaluate the roles of CYP3A and P-gp in K02 disposition. Male Sprague-Dawley rats (8-10 wk old, n = 3-6) were administered a single dose of K02 (10 mg/kg) i.v. or (30 mg/kg) p.o. with or without a concomitant oral dose of ketoconazole (20 mg/kg). Blood samples were collected from 2 min to 8 h after administration through a implanted jugular vein cannula. K02 plasma concentrations were determined by liquid chromatography/mass spectrometer/mass spectrometer analysis. Ketoconazole markedly raised the area under the curve of orally administered K02 from 9.4 +/- 4.4 to 102 +/- 24 mg . min/liter and decreased K02 oral plasma clearance from 3810 +/- 1620 to 306 +/- 60 ml/min/kg. With concomitant ketoconazole dosing, the changes of AUC of i.v. administered K02 (from 94 +/- 17 to 107 +/- 14 mg . min/liter) and clearance (from 110 +/- 22 to 95 +/- 13 ml/min/kg) were not significant, although K02 oral bioavailability increased from 2.9 +/- 1.4 to 31.0 +/- 7.5% (P < .001). In summary, ketoconazole, a dual inhibitor of CYP3A and P-glycoprotein, can effectively increase K02 oral bioavailability by inhibiting the CYP3A/P-gp absorption barrier in the small intestine.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9765344&dopt=Abstract ketoconazole Nizoral



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Origin of differences in susceptibility of Candida krusei to azole antifungal agents.

Marichal P, Gorrens J, Coene MC, Le Jeune L, Vanden Bossche H.

Division of Medicinal Chemistry and Pharmacology, Janssen Research Foundation, Beerse, Belgium.

Two Candida krusei isolates were used to compare the effects of fluconazole, ketoconazole and itraconazole on growth and ergosterol synthesis, and to measure intracellular drug contents. Fifty per cent inhibition (IC50) of growth was achieved at 0.05-0.08 microM itraconazole and 0.56-1.2 microM ketoconazole, whereas 91-->100 microM fluconazole was needed to reach the IC50 value. Similar differences in sensitivity to these azole antifungal agents were seen when their effects on ergosterol synthesis from [14C]acetate were measured after 4 h and 24 h of growth. However, when the effects of the azoles on ergosterol synthesis from [14C]mevalonate by subcellular fractions were measured, fluconazole was only 2.3-6.1 times less active than itraconazole, and the IC50 values for ketoconazole were almost similar to those obtained with itraconazole. These results indicate that differences in susceptibility to itraconazole and ketoconazole are unrelated to differences in affinity for the C. krusei cytochrome P450. The much lower growth-inhibitory effects of fluconazole can also be explained partly only by a lower affinity for the P450-dependent 14 alpha-demethylase. The differences in sensitivity of both C. krusei isolates appeared to arise from differences in the intracellular itraconazole, ketoconazole and fluconazole contents. Depending on the experimental conditions, these isolates accumulated 6-41 times more itraconazole than ketoconazole and the intracellular ketoconazole content was 3.0-19.0 times higher than that of fluconazole.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7477085&dopt=Abstract ketoconazole Nizoral