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At least 19 recordsLinked to original sources

PubMed1991

Effects of ranitidine and sucralfate on ketoconazole bioavailability.

Ketoconazole is an oral imidazole antifungal agent useful in the treatment of opportunistic fungal infections. Gastrointestinal absorption of this agent is variable and dependent on the presence of gastric acid. This study compared the effects of concomitant sucralfate administration with ranitidine administration on the pharmacokinetic disposition of a 400-mg ketoconazole dose. Six healthy male volunteers were randomized to receive 400 mg of ketoconazole alone, 1.0 g of sucralfate concomitantly with a 400-mg ketoconazole dose, or ranitidine, administered 2 h prior to a 400-mg ketoconazole dose to titrate to a gastric pH of 6. All subjects received all three regimens in crossover fashion. Gastric pH was measured continuously for 4 h after ketoconazole administration in all subjects by using a Heidelberg radiotelemetry pH capsule. Relative ketoconazole bioavailability was compared between treatments. With sucralfate, five of six subjects demonstrated a decrease in the peak drug concentration in serum as well as an increase in the time to peak concentration, indicating a delay in ketoconazole absorption. The mean area under the concentration-time curve from 0 to 12 h for ketoconazole following gastric alkalinization was significantly different from that of either ketoconazole alone or ketoconazole with sucralfate (P less than 0.01). Continuous gastric pH monitoring allowed correlation between the decrease in ketoconazole bioavailability observed with ranitidine and the increase in gastric pH. The apparent decrease in ketoconazole bioavailability observed with sucralfate appears to be caused by an alternative mechanism since a change in gastric pH was not observed. On the basis of these findings, separating the administration of ketoconazole and sucralfate should be considered to decrease the potential for interaction of sucralfate on ketoconazole bioavailability.

Adult↗

PubMed1992

Ketoconazole binds to the human androgen receptor.

Ketoconazole, an imidazole anti-fungal agent, has often produced features of androgen deficiency including decreased libido, gynecomastia, impotence, oligospermia, and decreased testosterone levels, in men being treated for chronic mycotic infections. Based on these potent effects on gonadal function in vivo as well as previous work in vitro demonstrating affinity of ketoconazole for receptor proteins for glucocorticoids and 1,25(OH)2 vitamin D3 and for sex steroid binding globulin (SSBG), the binding of ketoconazole to human androgen receptors (AR) in vitro was also examined. Ketoconazole competition with [3H]methyltrienolone (R1881) for androgen binding sites in dispersed, intact cultured human skin fibroblasts was determined at 22 degrees C. Fifty percent displacement of [3H]R1881 binding to AR was achieved by 6.4 +/- 1.8 (SE) x 10(-5) M ketoconazole. Additional binding studies performed with ketoconazole in the presence of increasing amounts of [3H]R1881 showed that the interaction of ketoconazole with AR was competitive when the data were analyzed by the Scatchard method. It should be noted, however, that the dose of ketoconazole required for 50% occupancy of the androgen receptor is not likely to be achieved in vivo, at least in plasma. Finally, androgen binding studies performed with other imidazoles, such as clotrimazole, miconazole, and fluconozole, revealed that in this class of compounds only ketoconazole appears to interact with the androgen receptor. Ketoconazole appears to be the first example of a non-steroidal compound which binds competitively to both SSBG and multiple steroid hormone receptors, suggesting that the ligand binding sites of these proteins share some features in common.

Cells, Cultured↗

PubMed1991

Effects of ketoconazole in hirsute women.

To determine the efficacy of ketoconazole in the treatment of hirsutism, clinical and hormonal effects of this agent were evaluated with a randomized, placebo-controlled, double-blind cross-over study design. Nine hirsute women were given ketoconazole (600 mg/day) or placebo for 6 months and then crossed over. The severity of hirsutism was assessed according to the scale of Ferriman & Gallwey. Baseline serum testosterone, dehydroepiandrosterone sulphate, progesterone, estradiol, basal and stimulated cortisol and 17-alpha hydroxyprogesterone were measured. Blood was also drawn for FSH and LH levels at 0, 30, 60, and 90 min of a GnRH stimulation test. The same parameters were determined following administration of placebo or ketoconazole for 6 months. The pretreatment (28.3 +/- 0.9) and post-placebo (27.7 +/- 1.4) Ferriman-Gallwey scores were significantly higher than the post-ketoconazole score (16.6 +/- 1.3, p less than or equal to 0.01). Basal and stimulated cortisol levels were not blunted after ketoconazole, but basal and stimulated 17-hydroxyprogesterone levels were significantly higher, indicating sufficient enzymatic inhibition. Serum dehydroepiandrosterone sulphate and testosterone levels were significantly lowered following ketoconazole (p less than or equal to 0.05). Although E2 levels did not change significantly at any time, E2:testosterone ratios were significantly higher after ketoconazole (p less than or equal to 0.01), and the LH:FSH area ratio was also significantly greater than 3 after ketoconazole. It is concluded that ketoconazole significantly alleviates hirsutism by inhibiting steroid synthesis.

Adult↗

PubMed1991

Study of lipids in dermatophytes. II. The effect of ketoconazole in the exponential stage of growth.

There was studied the effect of ketoconazole on the growth, the amount of ergosterol and the relative distribution of fatty acids in the sensitive strain MG-155 of M. gypseum and its two ketoconazole-resistant mutants UV-1 and UV-2 (induction by UV radiation) in the exponential stage growth. After three-day cultivation in the medium with ketoconazole (0.64 microgram.ml-1) there appeared 40% inhibition of growth in MG-155, 10% inhibition in UV-2 and only 4% inhibition UV-1. The amount of ergosterol decreased in MG-155, in both mutants the amount of ergosterol increased by the effect of ketoconazole (by more than 50%). The main saturate fatty acids are palmitic acid (10% and stearic acid (4%). The major fraction of unsaturate fatty acids is formed by linoleic acid (50%) and by oleic acid (4%). Ketoconazole does not affect the quality of fatty acids spectre, it changes only the size of the relative distribution of individual fatty acids. In this point of view, the mutant UV-2, and namely the mutant UV-1 (the higher degree of resistance) differ from the initial sensitive strain MG-155. Ketoconazole provokes in mutants a higher reduction of stearic acid fraction, of saturate fatty acids C greater than 18 and of triunsaturate fatty acids and it causes only minimum (4% for UV-1) decrease of oleic acid. The results of cultivations with postponed application of ketoconazole to the medium (on the 2nd the 1st day before the mycelium harvest) show in a decisive way that effect of ketoconazole is fully developed only on condition that ketoconazole is added to the medium simultaneously with the inoculum. There are discussed several conclusions with regard to the findings in the identical strains in stationary stage of growth.

Animals↗

PubMed1991

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

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.

Animals↗

PubMed1992

Ketoconazole inhibition of the bifunctional cytochrome P450c17 does not affect androgen formation from the endogenous lyase substrate. The catalytic site remains refractory in the course of intermediary hydroxyprogesterone processing.

The inhibition of the bifunctional steroidogenic cytochrome P450c17 (CYP17: steroid-17 alpha-hydroxylase/steroid-17,20-lyase) by the imidazole-type fungicide, [(+/-)-cis-1-acetyl-4-[4-[[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl- methyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazine) (ketoconazole), was investigated with the aim of differentiating between effects on androgen formation from exogenously added and endogenously produced 17 alpha-hydroxyprogesterone. Using microsomal membranes from rat testis, turnover of progesterone by P450c17 was competitively inhibited by ketoconazole with KI = 0.40 microM. Ketoconazole did not affect the linear relationship between the ratio of productive events (corresponding to androgen formation rates) versus abortive events (corresponding to 17 alpha-hydroxyprogesterone formation rates) and the sum of catalytic events. This was an indication that this inhibitor did not interfere with intermediate processing by P450c17. Androgen formation from exogenous but not from endogenous 17 alpha-hydroxyprogesterone was competitively inhibited by ketoconazole. The simultaneous conversion of 1 microM each of [3H]progesterone and 17 alpha-hydroxy[14C]progesterone was also reduced by ketoconazole. Calculation of 3H/14C ratios in the 17 alpha-hydroxyprogesterone and androgen fractions revealed that the endogenous 17 alpha-hydroxyprogesterone pool was metabolized to androgens at rates 6.4, 11.6, 17.6 and 21.2-fold faster than the exogenous pool in the presence of 0.5, 1, 2 and 4 microM ketoconazole, respectively; this value was only 4.0 in controls. It is concluded that ketoconazole inhibits turnover of steroid ligands only when they approach the P450c17 active site in a substrate-state and that inhibition of androgen formation from progesterone is due to inhibition of the first catalytic step only. A model is described in which the P450c17 active site is refractory towards ketoconazole when the intermediary steroid is retained and being processed at that site.

17-alpha-Hydroxyprogesterone↗

PubMed1991

Treatment of sarcoidosis-associated hypercalcemia with ketoconazole.

A 47-year-old patient presented with hypercalcemia secondary to sarcoidosis and was successfully treated with 1 year of corticosteroids leading to improvement in his hypercalcemia, hypercalcuria, and elevated levels of 1,25-dihydroxyvitamin D. Angiotensin-converting enzyme levels (ACE) normalized and serum creatinine improved. When hypercalcemia recurred after a 3-year symptom-free interval, the patient refused repeat corticosteroid treatment and was placed on ketoconazole (initially 600 and eventually 800 mg/d). Ketoconazole controlled the patient's hypercalcemia (serum calcium, 3.2 to 2.6 mmol/L [12.8 to 10.4 mg/dL]), but only the larger dose suppressed serum 1,25-dihydroxyvitamin D levels into the normal range. Hypercalcuria was markedly improved with ketoconazole, decreasing from a peak of 23 mmol/d (940 mg/d) to less than 8.7 mmol/d (350 mg/d) on a dose of 800 mg. However, serum ACE levels remained elevated on ketoconazole. An attempt to taper the ketoconazole after 1 year resulted in rapid recurrence of hypercalcemia (serum calcium, 2.8 mmol/L [11.1 mg/dL]) and hypercalcuria (urinary calcium excretion, 11 mmol/d [451 mg/d]). After a total of 2 years of ketoconazole treatment, his defect in calcium metabolism remains well controlled despite persistent elevation in ACE levels. Serum cortisol levels and liver function tests remain normal on therapy, although there has been a slight decrease in serum testosterone levels accompanied by some decrease in libido. These data suggest that long-term use of ketoconazole may be a safe and effective alternative to corticosteroid treatment for sarcoid-associated hypercalcemia. Further study is needed to determine whether the long-term side effects of ketoconazole therapy or its failure to control disease activity in sarcoidosis outweigh its advantages in avoiding the known side effects of glucocorticoids.

Calcitriol↗

PubMed1992

Oral ketoconazole prophylaxis for Candida infections during induction therapy for acute leukaemia in adults: more bacteraemias.

We determined whether ketoconazole prophylaxis might reduce Candida colonization and infections in adult patients with acute leukaemia. During first-remission induction therapy 50 patients were treated with 200 mg ketoconazole administered orally daily, while 57 patients received placebo in a double-blind, randomized trial. The duration of severe neutropenia (granulocytes less than 0.1 x 10(9) l-1) represented 36% of the study period in the ketoconazole group and 26% in the placebo group (P = 0.043). Although fewer patients presented with positive Candida surveillance cultures and serological evidence of Candida infection in the ketoconazole group compared to the placebo group, two candidaemias and one Trichosporum fungaemia were observed in the ketoconazole group. Moreover, significantly more bacteraemias were noted in the ketoconazole group (n = 37) than in the placebo group (n = 21) (P = 0.004). Thus, although oral ketoconazole prophylaxis might be associated with less Candida colonization and fewer seroconversions, it also resulted in more bacteraemias and longer duration of severe neutropenia, suggesting that caution should be exercised when ketoconazole (or related drugs) is given to this group of immunocompromised hosts.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1992

Pharmacokinetics/pharmacodynamics of ketoconazole-prednisolone interaction.

Ketoconazole is commonly used in patients with fungal infections during immunosuppressive therapy with prednisolone. Ketoconazole inhibits mixed function oxidases, enzymes responsible for the catabolism of prednisolone, and might, by that mechanism, increase prednisolone concentrations and thus, the immunosuppressive effect of prednisolone. On the other hand, ketoconazole has been found to bind to the glucocorticoid receptor and, thereby, to function as a glucocorticoid antagonist in cultured cell preparations. In order to establish whether ketoconazole enhances or attenuates the immunosuppressive effect of prednisolone, the influence of ketoconazole on the kinetics of prednisolone and on the delayed hypersensitivity response was assessed in mice. Ketoconazole increased prednisolone concentrations, measured by high pressure liquid chromatography, in mice given a single dose of prednisolone or a continuous prednisolone treatment for 17 days. At four different doses of prednisolone administered for 17 days, the glucocorticoid therapy-associated inhibition of the delayed hypersensitivity response to keyhole limpet hemocyanin was enhanced by ketoconazole. Thus, coadministration of ketoconazole with prednisolone increases the exposure to the steroid and enhances the immunosuppressive effect.

Animals↗

PubMed1991

The antiinflammatory effects of ketoconazole. A comparative study with hydrocortisone acetate in a model using living and killed Staphylococcus aureus on the skin of guinea-pigs.

Several reports have demonstrated the efficacy of topical ketoconazole in dermatologic conditions that are not exclusively related to fungi. Some basic pharmacologic studies have indicated effects of ketoconazole on cholesterol production in keratinocytes, on the 5-lipoxygenase enzyme, and on the metabolism of all-trans-retinoic acid in the skin. These observations have led to the hypothesis that topically applied ketoconazole may possess antiinflammatory properties. This hypothesis was tested in an animal model in which living and killed Staphylococcus aureus applied to the backs of guinea pigs resulted in inflammation with erythema and hyperkeratosis. Ketoconazole 0.5% or 2% was applied topically once daily in an ointment base, either as monotherapy or in combination with hydrocortisone acetate 1%. In addition, untreated, excipient-treated, and hydrocortisone acetate-treated animals were included in the study design. All groups consisted of 10 animals that were observed and scored daily up to 3 days after the experimental therapy was stopped. In the animal model involving killed bacteria (i.e., no infection), topical ketoconazole had antiinflammatory activity comparable to that of hydrocortisone acetate. The activity of ketoconazole on the skin of animals infected with living bacteria (i.e., active bacterial infection) was superior to that of steroid therapy, which suggests some antibacterial effect of topically applied ketoconazole. The combination therapy was highly active under both conditions. These results suggest that, apart from the known antimycotic effects of ketoconazole, this molecule might also have effects against gram-positive bacteria at the high concentrations obtained after local application.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Cutaneous↗

PubMed1991

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

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)

Adult↗

PubMedDate not supplied

Enhanced phagocytosis and intracellular killing of Pityrosporum ovale by human neutrophils after exposure to ketoconazole is correlated to changes of the yeast cell surface.

In seborrhoeic dermatitis an inflammatory response occurs secondary to large numbers of Pityrosporum yeasts appearing within and beneath the epidermis. To study the interaction between human neutrophils and P. ovale and any immunomodulating effect of antifungal agents, the yeast was exposed to ketoconazole and then incorporated into neutrophil monolayer assays. Phagocytosis was complement dependent and reached a maximum after 40 min. Ketoconazole at 25, 50 and 100 mg l-1 had no significant effect on phagocytosis of P. ovale. However, when yeast cells were pretreated with ketoconazole for 2 h before exposure to the phagocyte monolayer there was a significant enhancement of phagocytosis with increasing drug concentration. Intracellular killing of P. ovale was assessed by methylene blue dye exclusion. In the absence of ketoconazole, 5% of intracellular yeast cells were killed following internalization for 2 h. Pretreatment of yeast cells with ketoconazole at 10 and 100 mg l-1 for 2 h prior to ingestion significantly increased intracellular killing to a maximum of 23%. This study demonstrates that yeast cells of P. ovale are readily ingested by human neutrophils by a complement dependent process. Phagocytosis is enhanced if the organism is exposed to ketoconazole before opsonisation and ingestion. The inability of neutrophils to kill P. ovale is modulated in the presence of therapeutic concentrations of ketoconazole.

Cells, Cultured↗

PubMedDate not supplied

Prospective study of the safety and financial benefit of ketoconazole as adjunctive therapy to cyclosporine after heart transplantation.

In a prospective study of the relative safety and potential benefit of concomitant ketoconazole and cyclosporine after heart transplantation, 15 transplant recipients were followed up for up to 1 year (mean, 10.7 months) after ketoconazole was added to their immunosuppressive regimen of cyclosporine, prednisone, and azathioprine, and these patients were compared with a matched cohort over the same time. There was an 88% reduction in the mean (+/- SD) dose of cyclosporine, from 394 (115) mg/day to 47 (21) mg/day (p less than 0.0005) in the ketoconazole group, compared with an insignificant change in the control group. The projected annual cost of cyclosporine was reduced by 88%, with a 72% reduction in the projected cost of immunosuppressive drugs and prophylactic antifungal therapy, from a mean of $6800 to $1862 per year per transplant recipient in the ketoconazole-treated group. Other beneficial effects found over the study period included a significant reduction in the mean and diastolic systemic arterial pressure and a significant reduction in serum cholesterol. The mean total serum cholesterol fell from 265 (44) to 204 (38) mg/dl in the ketoconazole group but did not change significantly in the control group (p less than 0.005). Low-density lipoprotein cholesterol also fell from a mean of 167 (32) mg/dl to 112 (28) mg/dl (p less than 0.005). Renal function was not significantly affected by ketoconazole when compared with the control group. Ketoconazole and other drugs of potential use in organ transplant recipients should be evaluated for financial as well as for other potential clinical benefits in the long-term management of these patients.

Azathioprine↗

PubMed1991

Lack of pharmacokinetic and pharmacodynamic interactions between ketoconazole and prednisolone.

The effects of ketoconazole on the pharmacokinetics and pharmacodynamics of intravenous prednisolone (14.8 mg) were assessed in six healthy volunteers. Subjects were studied with and without receiving ketoconazole, 200 mg orally for 6 days. The addition of ketoconazole did not significantly change the clearance (96 +/- 11 versus 90 +/- 11 ml/hr/kg), mean residence time (4.29 +/- 0.43 versus 4.45 +/- 0.59 hours), volume of distribution (0.41 +/- 0.02 versus 0.40 +/- 0.02 L/kg), or plasma protein binding characteristics of prednisolone. The suppressive effects of prednisolone on serum cortisol, blood basophil, and helper T lymphocyte values, assessed by the ratio of the area under the curve (AUC) after prednisolone administration to the baseline AUC, was not altered significantly by ketoconazole. The 50% inhibitory concentration values derived from pharmacodynamic models developed to describe the direct suppressive effects of corticosteroids indicated no alteration in intrinsic sensitivity in the presence of ketoconazole. Ketoconazole does not appear to alter the pharmacokinetics or the pharmacodynamic response patterns of selected direct suppression effects of single low doses of prednisolone.

Adult↗

PubMed1992

Comparative study of ketoconazole 2% foaming gel and betamethasone dipropionate 0.05% lotion in the treatment of seborrhoeic dermatitis in adults.

Sixty-two patients with seborrhoeic dermatitis were treated topically with a 2% ketoconazole foaming gel or with a 0.05% betamethasone dipropionate lotion in a single-blind study for 4 months. Changes in the number of Pityrosporum ovale were scored by a mycologist. The investigator rated the severity of erythema, scaling and itching of the patients' scalp, eyelashes, nasolabial folds and thorax. In addition, both the investigator and the patients evaluated the treatments globally. At the end of treatment, the response rate for ketoconazole 2% foaming gel was significantly higher than that for betamethasone dipropionate 0.05% lotion according to the global evaluation by the physician (89 vs. 62%, p less than 0.05) and the patient (89 vs. 65%, p less than 0.05). Ketoconazole was also superior to betamethasone with reference to the evolution of the symptoms, irrespective of their localization. This efficacy manifested itself by a significant reduction of the number of P. ovale on the scalp in the ketoconazole group (p less than 0.001) compared to the betamethasone group, in which the count was hardly changed during therapy. The treatment was also better tolerated in the ketoconazole group (5 vs. 16 patients with side-effects, p less than 0.001). It is concluded that ketoconazole 2% foaming gel offers an excellent alternative to local corticosteroids in the treatment of seborrhoeic dermatitis.

Administration, Topical↗

PubMed1992

Effects of ketoconazole on the proliferation and cell cycle of human cancer cell lines.

The growth-inhibitory effects of ketoconazole, an antifungal agent which inhibits arachidonic acid lipoxygenases and cytochrome P-450 enzymes, were tested in human colon and breast cancer cell lines. In the serum independent HT29-S-B6 colon cell clone, ketoconazole reduced cell proliferation and [3H]thymidine incorporation in a dose-dependent fashion, with a 50% inhibitory concentration of approximately 2.5 microM. Flow cytometry showed an accumulation of cells in the G0-G1 phase of the cell cycle and a concomitant decrease of the percentage of cells in S phase. Ketoconazole also inhibited [3H]thymidine incorporation in the hormone-independent breast cancer cells MDA-MB-231 and Evsa-T, with respective 50% inhibitory concentration of approximately 13 and 2 microM. The mechanism of action of ketoconazole is unknown. However, another lipoxygenase inhibitor, BW755C, inhibited only weakly [3H]-thymidine incorporation and accumulated the cells in S and G2. Conversely, clotrimazole and SKF525A, inhibitors of cytochrome P-450 enzymes, had effects similar to those of ketoconazole on HT29-S-B6 cells whereas metronidazole and secnidazole, other azole derivatives which do not inhibit cytochrome P-450 enzymes, had no effect. The results suggest that cytochrome P-450 enzyme(s) activity(ies) could be implicated in the antiproliferative effects of ketoconazole.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗

PubMedDate not supplied

The effect of ketoconazole on endocrine and reproductive parameters in male mice and rats.

Ketoconazole has been shown to reduce steroidogenesis by inhibiting the cytochrome P-450 enzymes in these pathways. This finding, along with the observation that the compound reduces sperm motility, led us to study the effectiveness of ketoconazole as a male contraceptive agent administered in acute and chronic studies of both rats and mice. Four hours after a single administration, male rats showed significant reductions in both serum testosterone and corticosterone levels that completely recovered (testosterone) or nearly recovered (corticosterone) 24 hours after administration. Chronic administration of ketoconazole to male rats and mice resulted in steroid levels comparable with those of control animals. Epididymal sperm motility was only slightly reduced in male mice 4 hours after administration of the drug. No effect on sperm motility was noted after chronic administration in either species studied. In vitro exposure of epididymal sperm to ketoconazole resulted in a significant reduction of sperm motility. Breeding trials after ketoconazole administration resulted in normal fertility and fecundity even at the highest dosage studied. The lack of correlation between steroid levels and sperm immobilization, along with rapid in vivo and in vitro effects on sperm motility, suggests that the reduction in sperm motility is not related to a decrease in steroid levels. From these data, the authors conclude that ketoconazole is probably not a viable approach to the development of a male contraceptive.

Animals↗

PubMed1991

The antioxidant action of ketoconazole and related azoles: comparison with tamoxifen and cholesterol.

The azole antifungal drug ketoconazole was found to inhibit Fe(III)-ascorbate dependent lipid peroxidation using either rat liver microsomes or ox-brain phospholipid liposomes as the substrate. It also inhibited microsomal peroxidation induced by the Fe(III)-ADP/NADPH system. The related azoles, miconazole and clotrimazole, were much weaker inhibitors than ketoconazole. Ketoconazole was approximately equipotent with the triphenylethylene anticancer drug tamoxifen in the microsomal system and was almost as effective as 4-hydroxytamoxifen in the liposomal system. Ketoconazole introduced into phospholipid liposomes during their preparation inhibited Fe(III)-ascorbate induced lipid peroxidation to a greater extent than similarly introduced cholesterol, ergosterol or tamoxifen. Miconazole and clotrimazole were again poor inhibitors of lipid peroxidation in this system. These antioxidant effects of ketoconazole may be due to membrane stabilization in the systems used. The implications of our findings for the clinical applications of these drugs are discussed.

Animals↗