Intraindividual variability in male hepatic CYP3A4 activity assessed by alfentanil and midazolam clearance

Clinical investigations using isoform-selective probes to phenotype cytochr ome P450 activity and interaction studies using isoform-selective inhibitor s to determine P450 involvement in drug metabolism assume minimal interday variability in P450 activity. CYP3A4 is the most abundant human P450 isofor m and metabolizes approximately half of all therapeutic agents. This invest igation evaluated interday variability in hepatic CYP3A4 activity in males, using the clearances of midazolam and alfentanil as metabolic probes. Mida zolam (1 mg) followed 1 hour later by alfentanil (20 mu g/kg) were administ ered by in tra venous bolus to 9 nonsmoking male volunteers (ages 30 +/- 8 years). Drug administration was repeated 12 and 20 days later. Venous plasm a midazolam and alfentanil concentrations were determined by gas chromatogr aphy/mass spectrometry. Drug clearances were determined by noncompartmental and multiexponential analysis. There were no significant interday differen ces in plasma drug concentrations or clearances (3.9 +/- 1.4, 3.9 +/- 1.7, and 4.2 +/- 1.7 ml/kg/min for alfentanil, respectively, and 6.6 +/- 2.0, 7. 9 +/- 2.4, and 7.9 +/- 2.5 ml/kg/min for midazolam, respectively, on days 1 , 13, and 21 [mean +/- SD]). Interday variability in clearance was 13 % +/- 6% and 1 9 % +/- 12 % for alfentanil and midazolam, respectively. Interday variability in the clearance of these probes, and presumably hepatic CYP3A 4 activity, was small compared with interindividual variability Considerati on of interday variability in the hepa tic metabolism of CYP3A4 substrates does not appear significant in the design of clinical trials. (C) 1999 the American College of Clinical Pharmacology.