Application of semisimultaneous midazolam administration for hepatic and intestinal cytochrome P450 3A phenotyping

Objectives Determination of hepatic and intestinal cytochrome P450 (CYP) 3A activity is important, because CYP3A substrates show substantial variability in plasma concentrations as a result of variations in both hepatic and intestinal metabolism. The goals of this study were (1) to determine whether the hepatic and intestinal extraction ratios (ERH and ERG, respectively) of the CYP3A probe drug midazolam are different when determined after semisimultaneous administration, as compared with administration on separate occasions (traditional method), and (2) to evaluate the hepatic and intestinal metabolism of midazolam in the presence and absence of ketoconazole by the semisimultaneous method. Methods Midazolam pharmacokinetics was assessed in 12 healthy volunteers after administration of midazolam, 5 mg orally, followed at 6 hours by 2 mg given by intravenous infusion. Concentration‐time data were fitted to a combined oral‐intravenous infusion model by nonlinear regression (semisimultaneous method). Data from the semisimultaneous method were compared with those obtained after individual midazolam doses, 1 week apart (traditional approach). The effect of ketoconazole on midazolam pharmacokinetics after semisimultaneous administration was also determined in 4 healthy volunteers. Results There were no significant differences in bioavailability (0.343 ± 0.100 versus 0.343 ± 0.094), ERH (0.269 ± 0.064 versus 0.267 ± 0.077), and ERG (0.534 ± 0.135 versus 0.531 ± 0.124) between the traditional and semisimultaneous methods. As expected, ketoconazole markedly increased the mean bioavailability to 0.838 (2.4‐fold), the mean ERH was decreased 3.7‐fold, and the mean ERG was decreased 5.7‐fold. Conclusions Midazolam pharmacokinetic parameters that are specific to liver and intestinal metabolism were not different between the traditional and semisimultaneous methods. The semisimultaneous method also yielded expected marked changes in the parameters as a result of ketoconazole inhibition. Thus the semisimultaneous midazolam method appears to be a suitable approach to determine hepatic and intestinal CYP3A activity at baseline and with enzyme inhibition. Clinical Pharmacology & Therapeutics (2002) 72, 718–728; doi: 10.1067/mcp.2002.129068