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Hair Loss Study Abstract: Clinical pharmacokinetics of ketoconazole.
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Title
Clinical pharmacokinetics of ketoconazole.
Author
Daneshmend TK; Warnock DW
Address
Department of Therapeutics, University Hospital, Nottingham.
Source
Clin Pharmacokinet, 14: 1, 1988 Jan, 13-34
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.
Language of Publication
English
Unique Identifier
88165785
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