PT - JOURNAL ARTICLE AU - Maylee Chen AU - Anne N. Nafziger AU - Joseph S. Bertino, Jr. TI - Drug-Metabolizing Enzyme Inhibition by Ketoconazole Does Not Reduce Interindividual Variability of CYP3A Activity as Measured by Oral Midazolam AID - 10.1124/dmd.106.011742 DP - 2006 Dec 01 TA - Drug Metabolism and Disposition PG - 2079--2082 VI - 34 IP - 12 4099 - http://dmd.aspetjournals.org/content/34/12/2079.short 4100 - http://dmd.aspetjournals.org/content/34/12/2079.full SO - Drug Metab Dispos2006 Dec 01; 34 AB - Variable interindividual expression of cytochrome P450 3A presents a challenge in dosing drugs. The use of potent inhibitors of CYP3A such as ketoconazole has been explored to reduce the clearance of CYP3A substrates, thereby resulting in smaller dose requirements; however, the impact of CYP3A inhibition on interindividual variability has not been well characterized. Our objective was to examine the effect of ketoconazole inhibition on CYP3A metabolic variability as measured by the CYP3A biomarker oral midazolam. A single dose of midazolam (0.075 mg/kg) was administered to 19 healthy Caucasian adults (38.7 ± 8.8 years, nine male/10 female) at baseline and concurrently with ketoconazole (400 mg daily for 10 days) on day 6 or 9 of ketoconazole. Plasma samples were collected over 6 to 30 h. A paired t test and percent coefficient of variation (CV%) were used to evaluate differences in midazolam clearance and interindividual variability during both phases. Monte Carlo simulation was performed to determine probability distribution of area under the concentration-time curves (AUCs). Midazolam apparent oral clearance decreased by 89% (p < 0.0001) during inhibition. Cmax increased from 23 ng/ml (95% CI 19–29 ng/ml) to 55 ng/ml (95% CI 46–66 ng/ml), p < 0.0001. CV% increased from 41 to 58% from baseline to ketoconazole inhibition. AUCs [median (range)] were 0.20 mg · min/ml (0.05–0.81 mg · min/ml) and 1.94 mg · min/ml (0.25–25.4 mg · min/ml) at baseline and inhibition phase, with CV% of 41 and 61%, respectively. Ketoconazole decreased CYP3A activity but did not reduce interindividual variability. Use of a CYP3A inhibitor to standardize dosing of CYP3A substrates may not be feasible in clinical practice. The American Society for Pharmacology and Experimental Therapeutics