Prediction of midazolam-CYP3A inhibitors interaction in the human liver from in vivo/in vitro absorption, distribution, and metabolism data

The extent of decreases in apparent hepatic clearance and intrinsic hepatic clearance of midazolam (MDZ) after intravenous administration of MDZ with concomitant oral administration of cimetidine (CIM), itraconazole (ITZ), or erythromycin (EM) was predicted using plasma unbound concentrations and li ver unbound concentrations of inhibitors. When MDZ was concomitantly admini stered with CIM, the observed increase in MDZ concentration was successfull y predicted using inhibition constants assessed by human liver microsome an d liver-to-plasma unbound concentration ratios in rats. However, the extent of interaction with ITZ or EM was still underestimated even taking into ac count the concentrative uptake of inhibitors into liver. We could predict t he degree of "mechanism-based" inhibition by EM on the hepatic metabolism o f MDZ, after repeated administration of EM, by a physiological model incorp orating the amount of active enzyme as well as the concentration of inhibit or. The maximum inactivation rate constant and the apparent inactivation co nstant of EM on MDZ metabolism were 0.0665 min(-1) and 81.8 muM, respective ly. These kinetic parameters for the inactivation of the enzyme were applie d to the physiological model with pharmacokinetic parameters of EM and MDZ obtained from published results. Consequently, we estimated that cytochrome P450 3A4 in the liver after repeated oral administration of EM was inactiv ated, resulting in 2.6-fold increase in the plasma concentration of MDZ. Th e estimated extent of increase in MDZ concentration in our study correlated well with the observed value based on metabolic inhibition by EM from publ ished results.