Ketoconazole properties

Because ketoconazole has antiandrogenic properties, it is particularly suitable for women, in whom it has few effects on menstruation and does not cause hirsutism. In men, however, long-term inhibition of androgen production can be disruptive, especially if it leads to gynecomastia and hypogonadism. Combination with ami-noglutethimide and metyrapone has been advocated in order to avoid these effects (SEDA-17, 323). 

The intrinsic kinetic properties of the victim drug also influence the potential clinical consequences of an interaction. For orally administered medications that undergo significant presystemic extraction, impairment of clearance by a CYP inhibitor may produce increases in bioavailability (reduced presystemic extraction) as a consequence of reduced clearance. The effects may be particularly dramatic for CYP3A substrates (such as triazolam, midazolam, or buspirone) that undergo both hepatic and enteric presystemic extraction. As an example, coadministration of the CYP3A inhibitor ketoconazole with triazolam produced very large increases in area under the plasma concentration-time curve... 

The starting dataset used to develop the 3D quantitative structure property relationship (3D-QSPR) model consisted of 370 commercially available compounds. Activity data and 2D structures were retrieved from the Cerep database [18]. Inhibition of CYP 3A4 was reported as inhibition of the formation of 6y9-hydroxy-tes-tosterone [19]. Ketoconazole was used as reference compound so that all values are expressed as percentages. The log of the normalized CYP3A4 inhibition per-... 

B. Azole antifungals include systemic agents such as keto-conazole, fluconazole, itraconazole, and voriconazole. Topical agents used for the treatment of vaginal candidiasis and thrush include miconazole and clotrimazole. The pharmacologic properties of the systemic azoles differ considerably. Ketoconazole, the first oral azole developed, has poor bioavailability and requires an acidic environment for enhanced absorption. Thus, initial studies required ketoconazole to be administered with a cola to increase bioavailability. Fluconazole, unlike itraconazole and ketoconazole, is hydrophillic and has increased penetration across the blood-brain barrier. Fluconazole is also the only azole that is renally eliminated. 

The imidazoles comprise a large and diverse group of compounds with properties encompassing antibacterial (metronidazole), antiprotozoal (metronidazole), antifungal (clotrimazole, miconazole, ketoconazole, econazole) and anthelmintic (mebendazole) activity see Table 10.4. 

Ketoconazole has been replaced by itraconazole for the treatment of aU mycoses except when cost is the primary determinant. Itraconazole lacks ketoconazole s corticosteroid suppression, while retaining most of its properties and expanding the antifungal spectrum. 

Sterol 14-demethylase inhibitors with more potent activity and/or more optimal pharmacokinetic properties than ketoconazole and itraconazole need to be investigated in clinical trials to evaluate their potential for treating humans with Chagas disease... 

The imidazole moiety is very important in heterocyclic chemistry [10]. It is present in numerous natural products and also in many synthetic compounds. There are imidazole-based drugs such as ketoconazole 13 (antifungal properties) and losartan 14 (a drug against hypertension) (Fig. 12.1)... 

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