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The contribution of the gut is not routinely incorporated into in vitro-in vivo predictions of either clearance or drug-drug interactions, and this omission may partially explain the general underprediction trend often observed. In the current study, the metabolic ability of hepatic and intestinal pooled microsomes was compared for eight CYP3A substrates (midazolam, triazolam, diazepam, alprazolam, flunitrazepam, nifedipine, testosterone, and quinidine) and paclitaxel, tolbutamide, S-mephenytoin, and bufuralol as CYP2C8, CYP2C9, CYP2C19, and CYP2D6 probes, respectively. A general agreement in the type of kinetics was observed between the two systems for the substrates investigated. Of the 16 pathways investigated, 75% of K_m (S₅₀) values obtained in intestinal microsomes (5.9-769 μM) were within 2-fold of hepatic estimates. Irrespective of the cytochrome P450 (P450) investigated and normalization of V_max …