Nizoral
Comparative effects of ketoconazole on rat, dog and human testicular steroidogenesis.

De Coster R, Coene MC, Van Camp C, Van Camp K, Beerens D, Cools W.

Janssen Research Foundation, Beerse, Belgium.

Ketoconazole is an antifungal azole derivative which also inhibits the cytochrome P-450(17)alpha, catalyzing the conversion of progestins into androgens. The effects of ketoconazole on human, dog and rat testosterone biosynthesis were compared using short term incubations of dispersed testicular cells. The results showed that ketoconazole inhibited androgen biosynthesis at lower concentrations in dispersed human testicular cells (IC50: 0.08 mumol/l) than in canine (IC50: 0.1 mumol/l) and rat cells (IC50 greater than or equal to 0.2 mumol/l). Furthermore, they demonstrated that ketoconazole first inhibited the 17,20-lyase activity and then the 17-hydroxylation in rat and dog cells whereas only the 17-hydroxylation was affected in human cells.

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Body fluid and endometrial concentrations of ketoconazole in mares after intravenous injection or repeated gavage.

Prades M, Brown MP, Gronwall R, Houston AE.

Department of Surgical Sciences, College of Veterinary Medicine, University of Florida, Gainesville 32610-0136.

After single oral administration of ketoconazole (30 mg/kg bodyweight [bwt]) in 50 ml of corn syrup to a healthy mare, the drug was not detected in serum. Ketoconazole in 0.2 N HC1 was administered intragastrically to six healthy adult horses in five consecutive doses of 30 mg/kg bwt at 12 h intervals. Ketoconazole concentrations were measured in serum, synovial fluid, peritoneal fluid, cerebrospinal fluid (CSF), urine and endometrium. Mean peak serum ketoconazole concentration was 3.76 micrograms/ml at 1.5 to 2 h after intragastric administration. Mean peak synovial concentration was 0.87 micrograms/ml 3 h after the fifth dose. Similarly, mean peritoneal concentration peaked 3 h after the fifth dose at 1.62 micrograms/ml. Mean endometrial concentrations peaked at 2.73 micrograms/ml 2 h after the fifth dose. Ketoconazole was detected in the CSF of only one of the six mares at a concentration of 0.28 micrograms/ml 3 h after the fifth dose. The highest measured concentration of ketoconazole in urine was 6.15 micrograms/ml 2 h after the fifth dose. A single intravenous injection of ketoconazole (10 mg/kg bwt) was given to one of the six mares; the overall elimination rate constant was estimated at 0.22/h and bioavailability after oral administration was 23 per cent.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2731510&dopt=Abstract ketoconazole Nizoral



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The use of ketoconazole in prophylaxis of Candida sepsis.

Rietschel P, VanEgmond E, Lloyd L.

Department of Surgery, St. John Hospital, Detroit, MI 48236.

Candida sepsis has become an increasing problem in ICU patients with up to 50 per cent mortality rate. Ketoconazole, an oral antifungal agent, was used prophylactically in guinea pigs to see if this would prevent Candida sepsis. Absorption of ketoconazole has been stated to increase in an acid environment. Thirty-six guinea pigs were divided into three equal groups: group I received 1 cc normal saline, p.o.; group II received 10 mg/kg ketoconazole dissolved in 1 ml Maalox (Rorer Consumer; Fort Washington, PA); group III received 10 mg/kg ketoconazole in 1 ml in HCl, all given daily. Each animal received 10(8) colony forming units intravenously. The viability of the innoculum was confirmed by culture both pre- and postinjection. Each animal was observed daily for weight and ocular and skin lesions. Half of the animals were sacrificed on day seven and the remaining were sacrificed on day 14. Cultures, complete blood count (CBC), ketoconazole levels, and specimen histology were obtained. There was no difference between groups as to weight, leukocyte counts, skin or ocular lesions, or ketoconazole levels. Histologic analysis and quantitative cultures revealed little Candida invasion. In conclusion, Candida sepsis cannot be induced in healthy guinea pigs. The blood levels of ketoconazole were not affected by pH.

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Control of low density lipoprotein receptor gene promoter activity. Ketoconazole inhibits serum lipoprotein but not oxysterol suppression of gene transcription.

Takagi K, Alvarez JG, Favata MF, Trzaskos JM, Strauss JF 3rd.

Department of Obstetrics and Gynecology, University of Pennsylvania School of Medicine, Philadelphia 19104.

We have examined the effects of ketoconazole, a drug which inhibits enzymes involved in cholesterol biosynthesis and metabolism, on the suppressive effects of serum lipoproteins and 25-hydroxycholesterol on low density lipoprotein (LDL) receptor gene promoter activity. A LDL receptor promoter-chloramphenicol acetyltransferase (CAT) fusion gene construct (pLDLR-CAT 6500) was transfected into JEG-3 choriocarcinoma cells, and the transfected cells were cultured in the absence or presence of serum, LDL, or serum and 25-hydroxycholesterol. Serum, LDL, and serum + 25-hydroxycholesterol reduced chloramphenicol acetyltransferase activity in cells transfected with pLDLR-CAT 6500, whereas these treatments had no effect upon enzyme activity in cells transfected with a control construct (pSV2CAT). Ketoconazole (50 microM) overcame the effects of serum and LDL on suppression of pLDLR-CAT 6500 expression, but could not override the combination of serum + 25-hydroxycholesterol. Ketoconazole had no significant effect on expression of pSV2CAT. The drug inhibited cholesterol side chain cleavage enzyme in the cells, but appeared to have no impact on the ability of cells to take up LDL-carried lipids. Our observations are consistent with the idea that serum lipoprotein cholesterol is metabolized to an effector substance which acts to suppress LDL receptor gene transcription. The generation of this effector seems to be sensitive to ketoconazole.

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Skin blister fluid levels of ketoconazole during repetitive administration in healthy man.

Korting HC, Lukacs A, Schafer-Korting M, Heykants J, Behrendt H.

Ketoconazole administered orally is used in the treatment of superficial and deep mycoses. To evaluate its active concentrations in skin tissue, serum, suction blister fluid (SBF), and cantharides blister fluid (CBF) levels of total and non-protein bound ketoconazole were determined. In general, only the free drug is considered to be the active one. Six healthy subjects received 200 mg once daily for 5 days. Total ketoconazole concentrations were determined by HPLC. The unbound fractions of ketoconazole in SBF (2.3%) and CBF (1.2%) were calculated from plasma protein binding (99.0%). Before the ultimate dose, levels of unbound ketoconazole in SBF and CBF were 0.64 +/- 0.16 and 0.70 +/- 0.25 ng/ml and were thus in accordance with free ketoconazole serum levels (0.52 +/- 0.24 ng/ml; p greater than 0.05). Furthermore, following the ultimate dose, the areas under the blister fluid level-time curves of unbound ketoconazole did not differ from the respective areas under the serum level time curves, thus distribution equilibrium between serum and skin blister fluid was obtained. Peak concentrations of free ketoconazole were (SBF) 8.6 +/- 2.9 ng/ml and (CBF) 8.9 +/- 2.3 ng/ml. Free concentrations in SBF and CBF were far below the MIC values for dermatophytes and Candida ssp. reported in the literature, leaving the concentration-effect relationship of ketoconazole still open for discussion.

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Transscleral and transcorneal iontophoresis of ketoconazole in the rabbit eye.

Grossman R, Lee DA.

Jules Stein Eye Institute, Department of Ophthalmology, UCLA School of Medicine.

The authors assessed the efficacy of transscleral and transcorneal iontophoresis of ketoconazole as a method of drug delivery to the aqueous humor, vitreous, and cornea of the rabbit eye. Transscleral iontophoresis (4-6 mAmps for 15 minutes) achieved peak ketoconazole concentrations in the aqueous 1 hour after treatment (10.2 micrograms/ml) and remained at fungicidal therapeutic concentrations for 8 hours; in the vitreous, a peak concentration of 0.1 microgram/ml occurred between 1 and 2 hours posttreatment. Transcorneal iontophoresis (1.5 mAmps for 15 minutes) achieved peak corneal concentration of 27.6 micrograms/ml and peak aqueous concentrations of 1.4 micrograms/ml, both 1 hour after iontophoresis. Fungicidal therapeutic drug concentrations were sustained for 2 hours both in the cornea and in the aqueous. These concentrations were compared with those obtained after subconjunctival injection (peak values): 0.8 microgram/ml in aqueous, 5.9 micrograms/ml in cornea, and 0.7 microgram/ml in vitreous, all within 1 hour of injection. Aqueous and corneal concentrations were significantly higher after transscleral and transcorneal iontophoresis than subconjunctival injection (P less than 0.05). Iontophoresis is proposed as an effective means of delivering high concentrations of ketoconazole to the anterior segment of the eye.

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Inhibition of human adrenal androgen secretion by ketoconazole.

Weber MM, Luppa P, Engelhardt D.

Medizinische Klinik II, Universitat Munchen.

The effect of ketoconazole on adrenal androgen secretion was examined in 15 patients with elevated serum androgens. In a dose of 600 mg per day orally ketoconazole inhibited the biosynthesis of all measured androgens. The mean reduction in serum levels of dehydroepiandrosterone sulfate was 32%, of dehydroepiandrosterone 54%, of androstenedione 52%, and of testosterone 43%; mean serum levels of cortisol only fell by 19%. The reduction in serum androgen levels was first significant 24 h after beginning of treatment and persisted as long as the drug was administered. We conclude that ketoconazole inhibits adrenal androgen biosynthesis more pronouncedly than cortisol biosynthesis more pronouncedly than cortisol biosynthesis. This might be of clinical benefit in the treatment of hirsutism and other states of androgen hypersecretion.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2770183&dopt=Abstract ketoconazole Nizoral