Analysis of barrier function of intestinal drug-metabolizing enzymes and transporters

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It has been suggested that cytochrome P450 (CYP) 3A is expressed in the intestine as well as liver, and that the intestinal metabolism contributes largely to the oral bioavailability of tacrolimus and other CYP3A substrates in clinical studies. We investigated the contribution of intestinal metabolism to the first-pass effect of tacrolims in rats.Tacrolimus was administered intravenously, intraportally or intraintestinally to rats. Blood samples were collected over a 240-min period, and blood tacrolimus concentrations were measured. The extraction ratios of tacrolimus in the intestine and liver were investigated. The rate of absorption of tacrolimus in the intestine was rapid, and the drug was almost completely absorbed after intestinal administration. The bioavailability of tacrolimus was about 40% and 25% after intraportal and intraintestinal administration, respectively, indicating that tacrolimus is metabolized in both the intestine and the liver. Tacrolimus was significantly metabolized in the everted sac of the rat intestine.The present study suggested that the metabolism of tacrolimus in the intestine contributes to its extensive and variable first-pass metabolism following the oral administration. In addition, the exorption by P-glycoprotein, as well as metabolism by CYP3A in the intestine, may contribute to the first pass effects of some drugs, which are substrates of these proteins.