Effects of intestinal and hepatic metabolism on the bioavailability of tacrolimus in rats.

Purpose: Tacrolimus, an immunosuppressive agent, has poor and variable bioavailability following oral administration in clinical use. We investigated the contribution of intestinal metabolism to the first pass effect of tacrolimus in rats.

Methods: 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. In addition, the metabolism of tacrolimus in the everted sacs of the small intestine was examined.

Results: The rate of absorption of tacrolimus in the intestine was rapid, and tacrolimus 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. In addition, tacrolimus was significantly metabolized in the everted sacs of the rat intestine.

Conclusions: 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.