The structural basis for homotropic and heterotropic cooperativity of midazolam metabolism by human cytochrome P450 3A4.

Human cytochrome P450 3A4 (CYP3A4) metabolizes a significant portion of clinically relevant drugs and often exhibits complex steady-state kinetics that can involve homotropic and heterotropic cooperativity between bound ligands. In previous studies, the hydroxylation of the sedative midazolam (MDZ) exhibited homotropic cooperativity via a decrease in the ratio of 1'-OH-MDZ to 4-OH-MDZ at higher drug concentrations. In this study, MDZ exhibited heterotropic cooperativity with the antiepileptic drug carbamazepine (CBZ) with characteristic decreases in the 1'-OH-MDZ to 4-OH-MDZ ratios.

Simultaneous measurement of in vivo P-glycoprotein and cytochrome P450 3A activities.

Digoxin and midazolam are routinely used as probe drugs to measure in vivo activity of P-glycoprotein (P-gp) and cytochrome P450 3A4/5 (CYP3A), respectively. We investigated whether digoxin and midazolam could be coadministered to simultaneously determine P-gp and CYP3A activity without a significant pharmacokinetic interaction. In a randomized crossover design, digoxin (0.