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

Abstract

Studies were undertaken in 12 normal, male subjects to determine whether a metabolic interaction occurs between ketoconazole and mephenytoin. A single dose (400 mg) of ketoconazole produced a reduction in the 0-8 h urinary R/S ratio of mephenytoin following oral administration (100 mg) of racemic drug and after 28 daily doses the median value was further reduced to 42.9% of its baseline value. Within 7 days following discontinuation of ketoconazole the enantiomeric ratio had returned to its pre-study value. These findings are consistent with ketoconazole being a potent in vivo inhibitor of mephenytoin's 4-hydroxylation and confirm the ability of such an interaction to be predicted by in vitro studies with human liver microsomes. By contrast, ketoconazole had a much smaller effect on the 0-8 h urinary metabolic ratio of debrisoquine, indicating that ketoconazole has a selective inhibitory effect on different forms of cytochrome P-450.

Assessment of the CYP3A‐Mediated Drug Interaction Potential of Anacetrapib, a Potent Cholesteryl Ester Transfer Protein (CETP) Inhibitor, in Healthy Volunteers

“…Literature reports indicate that both dose and duration are key aspects when CYP3A inhibition by ketoconazole is considered. Specifically, single doses of ketoconazole 200 mg or 400 mg result in comparable amounts of CYP inhibition, but multiple doses (5 days) of 400 mg qd result in significantly increased CYP inhibition as compared with the results achieved with single 200‐mg or 400‐mg doses 10 , 11 . Four days of once‐daily therapy with ketoconazole 400 mg is associated with a nearly 16‐fold increase in midazolam AUC 7 and a 22‐fold increase in triazolam AUC, 12 both of which are very sensitive CYP3A4 substrates.…”

“…Four days of once‐daily therapy with ketoconazole 400 mg is associated with a nearly 16‐fold increase in midazolam AUC 7 and a 22‐fold increase in triazolam AUC, 12 both of which are very sensitive CYP3A4 substrates. Therefore, multiple doses of ketoconazole (5 days × 400 mg qd) were used to provide maximally increased CYP inhibition 10 , 11 . A ketoconazole treatment period of 28 days inhibits CYP activity by up to 37%, more than short‐term treatment.…”

Antipyrine as a probe for human oxidative drug metabolism: Identification of the cytochrome P450 enzymes catalyzing 4-hydroxyantipyrine, 3-hydroxymethylantipyrine, and norantipyrine formation*

“…Furafylline and fluvoxamine, both selective inhibitors of CYPlA2,25,26 were provided by U. Fuhr, Frankfurt, Germany, and K. Br@sen, Odense, Denmark, respectively. Sulfaphenazole, an inhibitor of CYP2C927 was supplied by Ciba-Geigy, Basel, Switzerland; ketoconazole, an inhibitor of CYP3A4,28 the CYP2C subfamily,27,29,30 and CYPlAl and CYP1A2,31 by Janssen, Beerse, Belgium. Mephenytoin (which is metabolized by CYP2C1932,33), was provided by Sandoz, Niirnberg, Germany.…”

Stereoselective and isozyme‐selective drug interactions

“…Additionally, they investigated the effect of ketoconazole on debrisoquine hydroxylation in the same subjects. 50 Each subject received a single dose of debrisoquin and mephenytoin to establish baseline activity of CYP2D6 and CYPMp, respectively. They then received oral ketoconazole 400 mg daiiy for 28 days.…”