Chemical formula: C₂₆H₂₈Cl₂N₄O₄ Molecular mass: 531.431 g/mol PubChem compound: 3823
Ketoconazole is a steroidogenesis inhibitor. Ketoconazole is an imidazole derivative that is a potent inhibitor of cortisol synthesis resulting from its ability to inhibit several cytochrome P450 enzymes in the adrenal glands. Ketoconazole inhibits primarily the activity of 17α-hydroxylase, but it also inhibits 11-hydroxylation steps, and at higher doses the cholesterol side-chain cleavage enzyme. Therefore, ketoconazole is an inhibitor of cortisol and aldosterone synthesis. Ketoconazole is also a potent inhibitor of androgens synthesis, inhibiting the activity of C17-20 lyase in the adrenals and also in Leydig cells.
Apart from adrenal blocking effect, ketoconazole may also have direct effects on corticotropic tumour cells in patients with Cushing’s disease.
Ketoconazole has a potent antimycotic action against dermatophytes and yeasts. Ketoconazole cream acts rapidly on the pruritus, which is commonly seen in dermatophyte and yeast infections. This symptomatic improvement often occurs before the first signs of healing are observed.
A study in 250 patients has shown that application twice daily for 7 days of ketoconazole 2% cream vs clotrimazole 1% cream for 4 weeks on both feet demonstrated efficacy in patients with tinea pedis (athlete’s foot) presenting lesions between the toes.
The primary efficacy endpoint was negative microscopic KOH examination at 4 weeks. Ketoconazole 2% treatment showed equivalent efficacy to 4 weeks clotrimazole 1% treatment. There was no evidence of relapse following treatment with ketoconazole cream at 8 weeks.
Ketoconazole is a weak dibasic agent and thus requires acidity for dissolution and absorption. Mean peak plasma concentrations of approximately 3.5 μg/ml are reached within 1 to 2 hours, following oral administration of a single 200 mg dose taken with a meal.
Cmax and AUC increase more than proportionally with dose. At steady state, mean peak concentrations of 1.7µg/mL to 15.6µg/mL were reported for total daily doses of 200mg to 1200mg.
Plasma concentrations of ketoconazole were not detectable after topical administration of ketoconazole cream in adults on the skin. In one study in infants with seborrhoeic dermatitis (n=19), where approximately 40 g of ketoconazole cream was applied daily on 40% of the body surface area, plasma levels of ketoconazole were detected in 5 infants, ranging from 32 to 133 ng/mL.
Plasma concentrations of ketoconazole were not detectable after topical administration of ketoconazole shampoo 2% on the scalp. Plasma levels were detected after topical administration of ketoconazole shampoo 2% on the whole body.
In vitro, the plasma protein binding is about 99% mainly to the albumin fraction. Ketoconazole is widely distributed into tissues; however, only a negligible proportion of ketoconazole reaches the cerebral-spinal fluid.
Ketoconazole is extensively metabolised to a large number of inactive metabolites. In vitro studies have shown that CYP3A4 is the major enzyme involved in the metabolism of ketoconazole.
The major identified metabolic pathways are oxidation and degradation of the imidazole and piperazine rings, oxidative O-dealkylation and aromatic hydroxylation.
Ketoconazole is a potent inhibitor of CYP3A4 and P-gp. Ketoconazole has not been demonstrated to induce its own metabolism.
Plasma elimination is biphasic with a half-life of 2 hours during the first 10 hours and 8 hours thereafter. The half-life of ketoconazole increases with dose and duration of treatment. At doses >400 mg/day, half-lives of 3 to 10 hours have been reported. About 13% of the dose is excreted in the urine, of which 2 to 4% is unchanged drug. The major route of excretion is through the bile into the intestinal tract.
Based on limited data, pharmacokinetics parameters (AUC, Cmax and half-life) of ketoconazole for doses of 5 to 10 mg/kg/days, corresponding approximately to daily doses of 200-800 mg, are similar in paediatric and adult population.
The pharmacokinetics of ketoconazole were not significantly different in patients with renal failure compared to healthy subjects.
No formal evaluation of the effect of age on the pharmacokinetics of Ketoconazole HRA has been performed. There are no data suggesting a need for a specific dose adjustment in this population.
In vitro data indicate that ketoconazole is a potent inhibitor of OATP1B1, OATP1B3, OAT3, OCT1 and OCT2 and to a lesser extent of OAT1 and BSEP. Inhibition of these different transporters at clinically relevant concentrations of ketoconazole cannot be excluded.
The toxicological profile of ketoconazole has been established from long term studies in rats and dogs.
Bone fragility and broken legs were reported in rats but were not observed in other species.
Consistent with the pharmacological action of ketaconazole, effects were observed on adrenal and gonads in rats and dogs.
Elevated liver enzymes and histological changes in the liver consisting in dose–related lipofuscin accumulation in hepatocytes were reported in rats and dogs after repeated administration of ketoconazole.
Electrophysiological studies have shown that ketoconazole inhibits the rapidly activating component of the cardiac delayed rectifier potassium current, prolongs the action potential duration, and may prolong the QT interval. However no modifications of ECG were recorded in dogs at daily doses up to 40 mg/kg administered for 12 months.
Ketoconazole was not genotoxic in vitro and in vivo. However, the genotoxic potential was not properly determined for the proposed dosing regimen in the treatment of endogenous Cushing’s syndrome. Ketoconazole is not carcinogenic.
In reproduction studies, ketoconazole impaired fertility in males and females. Doses of 25 mg/kg and higher in male rats and dogs produced sperm abnormalities and decreased fertility in rats. Ketoconazole at doses up to 40 mg/kg had no effects on female fertility in the rat, whilst doses of 75 mg/kg and higher decreased the pregnancy rate and the number of implantation sites. Doses of 80 and 160 mg/kg inhibited ovulation in immature rats. Ketoconazole at doses of 40 mg/kg/day and higher produces evidence of embryotoxicity and teratogenicity in rats and rabbits. Observed teratogenic effects were mainly skeletal anomalies, including cleft palate, brachydactylia, ectrodactylia and syndactylia. Treatment of juvenile rats for 30 day beginning at 21 days of age delayed the puberty onset. Effects on human reproduction cannot be excluded.
Studies in pregnant rats and in guinea pigs with 3H-ketoconazole indicate that ketoconazole crosses the placenta.
Effects in non-clinical studies were observed only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use.
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