Clinical Pharmacokinetics of Ketoconazole

Abstract

Ketoconazole, a synthetic imidazole antifungal, is effective for superficial fungal infections, genital candidosis and chronic mucocutaneous candidosis, and has been used in immunocompromised patients and advanced prostatic carcinoma. Absorption of ketoconazole is variable after oral administration, with large variability in peak serum concentrations. Antacids reduce, and food or dilute hydrochloric acid increase, absorption. Renal failure and bone marrow transplantation are associated with reduced absorption. Ketoconazole is not absorbed systemically after topical administration, and minimally absorbed from the vagina. Distribution of ketoconazole varies according to the tissue sampled, the underlying disease and the dose and duration of treatment. Ketoconazole does not cross the intact blood-brain barrier, and crosses to only a limited extent in fungal meningitis. Urinary concentrations of ketoconazole are usually low, but vaginal and vaginal tissue concentrations correlate with those in serum. Seminal fluid concentrations are inadequate for treatment of epididymitis. Ketoconazole is 83.7% plasma protein (mainly albumin) bound, and 15.3% is erythrocyte bound, resulting in only 1% of free drug. Animal studies indicate strong binding to the cytochrome P-450 mono-oxygenase complex. Extensive metabolism to inactive metabolites occurs, the products being mainly excreted in the faeces. Saturable hepatic first-pass metabolism is probable. The half-life of ketoconazole is dose-dependent, increases during long term treatment, suggesting auto-inhibition of metabolism. The kinetics after oral administration fit a 2-compartment model. Drug interactions of theoretical, if not practical, significance include warfarin, chlordiazepoxide, methylprednisolone, cyclosporin and drugs known to induce microsomal enzymes. In each case, some dosage adjustment for ketoconazole, or the interacting drug, may be required.

3-Ketocholanoic Acid Is the Major in Vitro Human Hepatic Microsomal Metabolite of Lithocholic Acid

“…Moreover, CYP3A4 inhibition by ketoconazole, a widely used drug for treating skin and antifungal infections, may be of clinical importance for lithocholic acid homeostasis. The currently recommended daily oral dose for ketoconazole is 200 to 400 mg (Daneshmend and Warnock, 1988;Schäfer-Korting, 1993;Gupta et al, 1994), and peak plasma concentrations of ketoconazole of 2.5 to 4 g/ml or 4.7 to 7.5 M were measured in healthy volunteers after administration of a single oral 200-mg dose (Heel et al, 1982;Gupta et al, 1994). This serum concentration is close to the highest concentration of ketoconazole used in the present study that produced maximal inhibition of lithocholic acid biotransformation.…”

Pharmacokinetics and bioavailability of fluconazole in two groups of males with human immunodeficiency virus (HIV) infection compared with those in a group of males without HIV infection

“…There have been suggestions that the pharmacokinetics of ketoconazole, another imidazole antifungal drug, may be dose dependent (8). Recently, similar suggestions have been made about the pharmacokinetics of another imidazole, itraconazole (2).…”

“…To date, changes in the disposition of some substances, including folic acid (16) and clindamycin (13), have been reported. It has been reported that the absorption of ketoconazole is decreased in the presence of a high gastrointestinal pH (3,8,20), a condition which can occur in people with HIV infection because of achlorhydria, although this does not appear to occur with fluconazole (3).…”

Effects of ketoconazole on the polymorphic 4‐hydroxylations of S‐ mephenytoin and debrisoquine.

“…For example, in vivo drug interactions in man have been noted with cyclosporin, chlordiazepoxide, methylprednisol, ne and antipyrine (Daneshmend & Warnock, 1988 (Hall et al, 1987). However, the ability of ketoconazole to impair the in vivo metabolism of the anticonvulsant has not been described.…”