Abstract

To select high bioavailability compounds, it is necessary to predict the first-pass metabolism in the intestine. However, in vitro-in vivo predictions of the intestinal metabolism have proven both challenging and less definitive. The purpose of this study was to investigate prediction of intestinal first-pass metabolism in humans using cynomolgus monkeys. First, we investigated intrinsic metabolic activities in intestinal microsomes of monkeys (MIM) and humans (HIM) (CL_{int, MIM} and CL_{int, HIM}, respectively) of 18 CYP3A substrates. The CL_{int, MIM} values were found to be relatively high and showed excellent correlation with the CL_{int, HIM} values. Subsequently, we determined the plasma concentrations of 9 CYP3A substrates (buspirone, carbamazepine, diazepam, felodipine, midazolam, nicardipine, nifedipine, saquinavir, and verapamil) in monkeys after an oral dose of 2 mg/kg with or without an oral dose of 5 mg/kg ketoconazole and calculated AUC_(+vehicle)/AUC_{(+ketoconazole)}, defined as F_{g, monkey(observed)}; we confirmed that the dose of ketoconazole inhibited only intestinal CYP3A metabolism by preliminary in vitro and in vivo experiments using ketoconazole. The F_{g, monkey(observed)} was lower than the F_{g, human(observed)} for most compounds, but moderate correlation was observed. Furthermore, using these data, we established a new methodology to estimate F_{g, human(predicted)} more precisely on the basis of the assumption that intestinal physiological conditions other than intrinsic metabolic activity would be the same between monkeys and humans. In conclusion, the in vivo model using cynomolgus monkeys in this study is useful for prediction of intestinal first-pass metabolism by CYP3A in humans because it was able to predict F_{g, human} of all nine compounds investigated.