In vitro and in vivo intestinal and hepatic oxidative metabolism of typical cytochrome P450 3A substrates, midazolam, nifedipine, and quinidine, in minipigs: a comparison with humans, monkeys, and dogs.

This study evaluated intestinal and hepatic first-pass metabolism of CYP3A substrates (midazolam, nifedipine, and quinidine) in minipigs and compared results with in vivo data reported for humans, monkeys, and dogs, and with in vitro data generated herein, to investigate interspecies differences and the feasibility of human extrapolation.In vivo pharmacokinetics were assessed in minipigs following intravenous and oral administration. Intestinal and hepatic intrinsic clearance were measured using microsomes from humans, minipigs, monkeys, and dogs.Across four species, the intestinal extraction ratio (Eg) correlated more strongly with oral bioavailability (F) than did the hepatic extraction ratio (Eh), indicating that intestinal first-pass extraction mainly determines F; in vivo and in vitro-predicted Eh correlated only when dogs were excluded. Minipig first-pass metabolism resembled that of humans for midazolam but showed strong substrate dependence, with a higher F for nifedipine and a higher Eg and lower F for quinidine; monkeys and dogs likewise deviated from humans in a substrate-dependent manner.Integrating multi-species in vitro and in vivo data yielded only preliminary, exploratory correlations; quantitative extrapolation from a single species remains limited, and improving the prediction of human first-pass metabolism will require integration with human-based in vitro models.