Ketoconazole (Nizoral)
Classification:
Antiinfective Agents
» Antifungals
» Azole antifungals
Dermatological Agents
» Topical Antiinfectives
» Antifungals
Description: Ketoconazole is an imidazole antifungal agent. Other agents in this group include clotrimazole, fluconazole, itraconazole, miconazole as well as many other topical agents. Within this group of antifungal agents, ketoconazole is unique in its ability, at doses higher than those required for antifungal activity, to inhibit the synthesis of adrenal steroids. Fluconazole, itraconazole, and ketoconazole can reduce the clearance of drugs metabolized via the hepatic mixed-function oxidase system, although ketoconazole is more potent in this regard. Ketoconazole was approved by the FDA in 1981 and is available in oral tablets, a 2% topical cream, and a 2% shampoo. On October 10, 1997, Nizoral® AD (ketoconazole 1% shampoo) was approved as an over-the-counter product for the treatment of dandruff. The Nizoral® oral tablets came off patent in 1999. In November 2004, a topical ketoconazole foam (Extina™, by Connetics) for seborrheic dermatitis was deemed unapprovable by the FDA because it was not superior to placebo foam in clinical trials.
Mechanism of Action: Like other azole antifungals, ketoconazole exerts its effect by altering the fungal cell membrane. Ketoconazole inhibits ergosterol synthesis by interacting with 14-alpha demethylase, a cytochrome P-450 enzyme that is necessary for the conversion of lanosterol to ergosterol, an essential component of the membrane. In contrast, amphotericin B binds to ergosterol after it is synthesized. Inhibition of ergosterol synthesis results in increased cellular permeability, which causes leakage of cellular contents. Ketoconazole does not appear to have the same effects on human cholesterol synthesis. Other antifungal effects of azole compounds have been proposed and include: inhibition of endogenous respiration, interaction with membrane phospholipids, and inhibition of yeast transformation to mycelial forms. Other mechanisms may involve inhibition of purine uptake and impairment of triglyceride and/or phospholipid biosynthesis. At higher concentrations, ketoconazole may have a direct physiochemical effect on the fungal cell membrane, which leads to a fungicidal action. In vitro, ketoconazole prevents Candida from forming pseudohyphae and also enhances phagocytosis of the fungi. Azole compounds, including ketoconazole, have a broad spectrum of antifungal activity against common fungal pathogens including Blastomyces dermatitidis, Candida species, Cryptococcus neoformans, Coccidioides immitis, Histoplasma capsulatum, Paracoccidioides brasiliensis, and Sporothrix schenckii.
Ketoconazole possesses actions that may make it useful in conditions other than fungal infections. Ketoconazole can inhibit sterol synthesis in humans including the synthesis of aldosterone, cortisol, and testosterone. Ketoconazole’s effects on testosterone synthesis occur at lower doses than do the effects on cortisol synthesis; doses of of 200 - 400 mg/day can inhibit testosterone secretion and doses of 400 - 600 mg/day have been shown to inhibit cortisol synthesis. Ketoconazole acts at many of same steps as metyrapone and, in some sites, has been shown to be a more potent inhibitor. Both ketoconazole and metyrapone affect multiple steps in the steroid-synthesis pathway, while finasteride appears to work at a single site. Ketoconazole has been used successfully for treating advanced prostate cancer. Finally, ketoconazole is a known potent inhibitor of thromboxane synthesis and has been used clinically to prevent ARDS in patients at high risk of this syndrome.
Pharmacokinetics:
Oral Ketoconazole: Ketoconazole is dissolved in gastric secretions and converted to the hydrochloride salt prior to rapid absorption from the stomach. Bioavailability of oral ketoconazole is a function of intragastric pH; an acidic environment is necessary for ketoconazole absorption. The concurrent administration of food with oral ketoconazole can lead to increased absorption either by increasing bile secretions, which increase the rate/extent of ketoconazole dissolution, or by delaying gastric emptying. The peak plasma concentration (Cmax) occurs between 1 - 4 hours after the oral dose is taken. After a 200 mg dose, the Cmax range is from 4.2 - 6.2 mcg/ml in healthy fasting adults to 1.5 - 4.5 mcg/ml in healthy non-fasting adults. Bioavailability of ketoconazole in an oral suspension form is greater than with the tablet. There is significant interindividual variation in peak plasma concentrations and AUCs from oral doses of ketoconazole. Ketoconazole may undergo saturable first-pass metabolism since bioavailability of lower doses is relatively poor compared with that of higher doses. Ketoconazole is widely distributed into most body fluids, although CNS penetration is unpredictable and usually minimal. In animal studies, it crosses the placenta and is distributed into milk. Protein binding is 84 - 99%, mainly to albumin.
Ketoconazole Shampoo (Shampoo 2 %) 
Ketoconazole plasma concentrations decline in a biphasic manner. Initial phase half-life is approximately 2 hours, and the terminal phase half-life is approximately 8 hours. The effect of renal or hepatic impairment on plasma concentrations and half-life is unclear. Ketoconazole is partially metabolized through oxidation, dealkylation, and aromatic hydroxylation. Most of the ketoconazole and its metabolites are excreted into the bile and then the feces. The rest is excreted in the urine. In a study involving fasting adults with normal renal function, about 57% of a 200 mg oral dose of ketoconazole was excreted in the feces within 4 days. Between 20 - 65% of the ketoconazole excreted in the feces was unchanged drug. Within 4 days, approximately 13% of the dose was excreted in the urine; approximately 2 - 4% of this portion was as unchanged ketoconazole.
Topical Ketoconazole: Topical ketoconazole does not have significant systemic absorption. Repeated topical application of ketoconazole 2% shampoo, however, will lead to absorption of the drug into hair keratin. Small amounts of intravaginal ketoconazole are absorbed systemically. Peak plasma concentrations in women receiving ketoconazole as a 400 mg vaginal suppository ranged from 0 - 20.7 ng/mL.
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References
. Como JA, Dismukes WE. Oral azole drugs as systemic antifungal therapy. N Engl J Med 1994;330:263 - 72.
. Borgers M. Mechanism of action of antifungal drugs, with special reference to the imidazole derivatives. Rev Inf Dis. 1980;2:520 - 34.
. Sonino N. The use of ketoconazole as an inhibitor of steroid production. N Engl J Med 1987;317:812 - 8.
. Pont A, Williams PL, Loose DS et al. Ketoconazole blocks adrenal steroid synthesis. Ann Intern Med 1982;97:370 - 2.
. Trachtenberg J, Pont A. Ketoconazole therapy for advanced prostate cancer. Lancet 1984:433 - 5.
. Yu M, Tomasa G. A double-blind, prospective, randomized trial of ketoconazole, a thromboxane synthetase inhibitor, in the prophylaxis of the adult respiratory distress syndrome. Crit Care Med 1993;21:1635 - 42.
[ Revised 6/14/2006 11:04:00 AM ]
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