It is known that CYP3A4, CYP2C9, and CYP2C19 are the enzymes involved in the metabolism of drug A. The estimated fm,CYP3A4, fm,CYP2C9, and fm,CYP2C19 are 0.1, 0.2, and 0.7, respectively, based on the...

It is known that CYP3A4, CYP2C9, and CYP2C19 are the enzymes involved in the metabolism of drug A. The estimated fm,CYP3A4, fm,CYP2C9, and fm,CYP2C19 are 0.1, 0.2, and 0.7, respectively, based on the clearance values obtained from recombinant enzyme systems. However, a clinical DDI study with itraconazole indicated that drug A is metabolized primarily by CYP3A4 and to a lesser extent by CYP2C9 and CYP2C19, with an estimated fm,CYP3A4 of 0.8 using PBPK modeling and simulation. Why may there be a difference between prediction from in vitro vs. in vivo?