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

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