In vitroandin vivosmall intestinal metabolism of CYP3A and UGT substrates in preclinical animals species and humans: species differences

Abstract

Intestinal first-pass metabolism has a great impact on the bioavailability of cytochrome P450 3A4 (CYP3A) and/or uridine 5'-diphosphate (UDP)-glucoronosyltranferase (UGT) substrates in humans. In vitro and in vivo intestinal metabolism studies are essential for clarifying pharmacokinetics in animal species and for predicting the effects of human intestinal metabolism. We review species differences in intestinal metabolism both in vitro and in vivo. Based on mRNA expression levels, the major intestinal CYP3A isoform is CYP3A4 for humans, CYP3A4 (3A8) for monkeys, CYP3A9 for rats, cyp3a13 for mice, and CYP3A12 for dogs. Additionally, the intestinal-specific UGT would be UGT1A10 for humans, UGT1A8 for monkeys, and UGT1A7 for rats. In vitro and in vivo intestinal metabolism of CYP3A substrates were larger in monkeys than in humans, although a correlation in intestinal availability between monkeys and humans has been reported. Little information is available regarding species differences in in vitro and in vivo UGT activities; however, UGT-mediated in vivo intestinal metabolism has been demonstrated for raloxifene in humans and for baicalein in rats. Further assessment of intestinal metabolism, particularly for UGT substrates, is required to clarify the entire picture of species differences.

Gut Wall Metabolism. Application of Pre-Clinical Models for the Prediction of Human Drug Absorption and First-Pass Elimination

“…Alternatively, it may reflect significant differences in DMEs expressed across species in the gut wall. Certainly, metabolism studies in preclinical species have reported marked differences when compared to human, depending upon the CYP450 subfamily of interest (79). This highlights an ongoing challenge associated with interpretation of complex in vivo data, in particular, quantifying the exact contribution of intestinal metabolism indirectly from more conventional IV and oral dosing strategies (30,71).…”

“…With raloxifene, very high extraction was observed in human intestines whereas moderate extraction was reported in rat (86). Conversely, with morphine, moderate extractions were seen in both rats and humans (79). Recently, Furukawa and co-workers assessed the in vivo intestinal availability of several human UGT substrates across rat, dog, monkey and humans (87).…”

“…Here, the goal is to extrapolate intestinal availability in humans from the most relevant animal model, or if necessary directly from human intestinal metabolism data that has been generated in vitro (22,23,27,29). The latter consideration is particularly important given that patterns of phase I and II DME expression in the intestine can differ markedly between species (63,79,87). Although research into IVIVE of intestinal metabolism data is evolving (88), it is still some way behind the established models used for the liver (22,23,28,29).…”

“…1, (15,25,(74)(75)(76)(77)(78)(79)(80)(81) and references included therein). With the CYP450 substrates, excepting tacrolimus (F a ∼15%), most of the drugs assessed are believed to exhibit good oral absorption in man (≥80% (25) data supplemental).…”

Relationship between low midazolam metabolism by cytochrome P450 3A in mice and the high incidence of birth defects

“…Mouse CYP3A11 is homologous to human CYP3A4 and is constitutively expressed in the liver of adult mice, wherein it plays a central role in drug metabolism (Sakuma et al, 2000;Li et al, 2009). CYP3A13 is upregulated in the small intestine and has important effects on drug metabolism in the gastrointestinal tract (Martignoni et al, 2006;Komura and Iwaki, 2011). Mouse CYP3A16 corresponds to human CYP3A7.…”