Ketoconazole - How It Works
Clinical pharmacology details from the US FDA-approved label: how Ketoconazole works in your body, how it's absorbed, how long it stays active, and how it's eliminated.
CLINICAL PHARMACOLOGY Pharmacokinetics Absorption Ketoconazole is a weak dibasic agent and thus requires acidity for dissolution and absorption.
Mean peak plasma concentrations of approximately 3.5 mcg/mL are reached within 1 to 2 hours, following oral administration of a single 200 mg dose taken with a meal.
Oral bioavailability is maximal when the tablets are taken with a meal.
Absorption of ketonazole tablets is reduced in subjects with reduced gastric acidity, such as subjects taking medications known as acid neutralizing medicines (e.g. aluminum hydroxide) and gastric acid secretion suppressors (e.g.H2-receptor antagonists, proton pump inhibitors) or subjects with achlorhydria caused by certain diseases. (See Section: PRECAUTIONS: DRUG INTERACTIONS .) Absorption of ketoconazole under fasted conditions in these subjects is increased when ketoconazole tablets are administered with an acidic beverage (such as non-diet cola).
After pretreatment with omeprazole, a proton pump inhibitor, the bioavailability of a single 200 mg dose of ketoconazole under fasted conditions was decreased to 17% of the bioavailability of ketoconazole administered alone.
When ketoconazole was administered with non-diet cola after pretreatment with omeprazole, the bioavailability was 65% of that after administration of ketoconazole alone.
Distribution 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 reaches the cerebrospinal fluid.
Metabolism Following absorption from the gastrointestinal tract, ketoconazole tablets are converted into several 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 the piperazine rings, by hepatic microsomal enzymes.
In addition, oxidative 0-dealkylation and aromatic hydroxylation does occur.
Ketoconazole has not been demonstrated to induce its own metabolism.
Elimination Elimination from plasma is biphasic with a half-life of 2 hours during the first 10 hours and 8 hours thereafter.
Approximately 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 with about 57% being excreted in the feces.
Special Populations Patients with Hepatic or Renal Impairment In patients with hepatic or renal impairment, the overall pharmacokinetics of ketoconazole was not significantly different when compared with healthy subjects.
Pediatric Patients Limited pharmacokinetic data are available on the use of ketoconazole tablets in the pediatric population.
Measurable ketoconazole plasma concentrations have been observed in pre-term infants (single or daily doses of 3 to 10 mg/kg) and in pediatric patients 5 months of age and older (daily doses of 3 to 13 mg/kg) when the drug was administered as a suspension, tablet or crushed tablet.
Limited data suggest that absorption may be greater when the drug is administered as a suspension compared to a crushed tablet.
Pharmacokinetics
Pharmacokinetics Absorption Ketoconazole is a weak dibasic agent and thus requires acidity for dissolution and absorption. Mean peak plasma concentrations of approximately 3.5 mcg/mL are reached within 1 to 2 hours, following oral administration of a single 200 mg dose taken with a meal. Oral bioavailability is maximal when the tablets are taken with a meal. Absorption of ketonazole tablets is reduced in subjects with reduced gastric acidity, such as subjects taking medications known as acid neutralizing medicines (e.g. aluminum hydroxide) and gastric acid secretion suppressors (e.g.H2-receptor antagonists, proton pump inhibitors) or subjects with achlorhydria caused by certain diseases. (See Section: PRECAUTIONS: DRUG INTERACTIONS .) Absorption of ketoconazole under fasted conditions in these subjects is increased when ketoconazole tablets are administered with an acidic beverage (such as non-diet cola). After pretreatment with omeprazole, a proton pump inhibitor, the bioavailability of a single 200 mg dose of ketoconazole under fasted conditions was decreased to 17% of the bioavailability of ketoconazole administered alone. When ketoconazole was administered with non-diet cola after pretreatment with omeprazole, the bioavailability was 65% of that after administration of ketoconazole alone.