Intestinal Cytochrome P450 and Response to Rifampicin in Rabbits

Abstract

Properties of cytochrome P450 (P450) in rabbit intestines have been investigated to assess the possibility of an experimental model for human intestinal oxidation of drugs. Significant amounts of P450 and cytochrome b5 and activities of NADPH-cytochrome P450 reductase were detected in microsomes from rabbit duodenal, jejunal, ileac and colon mucosa. All the small intestinal fractions mediated phenytoin, dextromethorphan and testosterone oxidations. Several P450 forms belonging to the CYP1A, CYP2C, CYP2D and CYP3A, but not CYP2B and CYP2E, subfamilies were detected in these tissues by Western blotting. A good correlation was observed between immunodetectable levels of CYP3A and activities of testosterone 6beta-hydroxylation. Small intestine, but not colon, CYP3A levels were increased by the pretreatment of rabbits with rifampicin (50 mg/kg for 4 days, p.o.). The extent of the increase was similar between duodena and livers. These properties of rabbit intestinal P450s were comparable to those of human intestine. These phenomena suggest the possibility that the rabbit is a beneficial in vivo model for the assessment of drug interaction occurring at the first pass of drugs ingested.