Ketoconazole is variably absorbed when administered orally in dogs.7 In people, ketoconazole absorption is increased with increased gastric acidity.8 No studies in dogs have examined the effect of a fed or fasted state on ketoconazole absorption, but as in people, it is
recommended to be given with food. In people, gastric acid suppression therapy—such as antacids, H2-receptor antagonists (cimetidine, famotidine), or proton pump inhibitors (omeprazole)—decreases ketoconazole absorption.
So concurrent administration of these drugs in animals receiving ketoconazole is also not recommended.
Ketoconazole is highly protein-bound (> 98%) and penetrates poorly into protected areas such as the central nervous system
(CNS), anterior chamber of the eye, and prostate.1 It is eliminated primarily by hepatic metabolism, with a half-life of about two hours in mongrel dogs.
No data are available on the pharmacokinetics of ketoconazole in cats.
Drug interactions and adverse effects
Since ketoconazole inhibits the metabolizing enzyme CYP3A12 in dogs, adverse effects can occur if it is given concurrently
with drugs metabolized by CYP3A12.9 The metabolism of the concomitant drugs is decreased, so toxicosis can occur because of drug accumulation.
Ketoconazole also inhibits the p-glycoprotein (Pgp) efflux pump present in numerous anatomical locations, including, but not
limited to, the gastrointestinal tract, liver, and blood-brain barrier.10 Pgp actively secretes absorbed substrates back into the lumen of the intestines (decreasing drug absorption), back into
the lumen of the brain capillary (an active component of the blood-brain barrier), and into the bile canaliculus (active biliary
secretion). The consequences of inhibiting the Pgp efflux pump include increased oral bioavailability of Pgp substrates, increased
penetration of Pgp substrates into the CNS, and decreased biliary secretion of Pgp substrates. A thorough review of Pgp substrates
and inhibitors has been previously published.11
Ketoconazole's inhibition of CYP3A12 and Pgp has been used therapeutically to decrease the dose of cyclosporine needed to
achieve targeted concentrations in both dogs and cats.12,13 Ketoconazole may decrease the elimination of cisapride, vincristine, diltiazem, lidocaine, buspirone, quinidine, some benzodiazepines,
and fentanyl, resulting in toxicity of the concurrently administered drug if dosages are not adjusted. Long-term phenobarbital
administration increases ketoconazole metabolism and may require increased ketoconazole dosages to maintain similar efficacy.
Other adverse effects associated with ketoconazole include nausea, anorexia, and vomiting; they occur more frequently at higher
dosages.1 Pruritus, alopecia, lightening of the coat, and weight loss can occur with long-term therapy.1
Slight to moderate increases in serum hepatic enzyme activities can also occur with long-term therapy, which may not be accompanied
by hepatic injury. However, large increases in serum hepatic enzyme activities accompanied by elevated serum bilirubin concentrations
may be indicative of hepatic injury. So routine monitoring of serum hepatic enzyme activities during long-term therapy is
warranted. Cats may be more sensitive to hepatotoxicosis,1 but with the lack of pharmacokinetic studies in cats, it is unclear whether this is truly an increased sensitivity or whether
the toxicosis is due to inappropriate dose recommendations. Idiosyncratic (non-dose-dependent) hepatotoxicosis has also been
reported in animals.1
Ketoconazole is teratogenic and not recommended for use in pregnant or lactating animals.14 Inhibition of testosterone has resulted in gynecomastia, impotence, and azoospermia in people. Cortisol production is also
inhibited by ketoconazole, more so in dogs than in cats.1,15 Cataract formation has also occurred in dogs with long-term administration of ketoconazole (average duration of therapy