Interplay between in tasting and liver for the first-pass metabolism of orally administered drugs

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Tacrolimus 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. 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 26% after intraportal and intraintestinal administration, respectively, indicating that tacrolimus is metabolized in both the intestine and the liver, and that the metabolism of tacrolimus in the intestine contributes to its extensive and variable first pass metabolism following the oral administration. Furthermore, the effects of renal failure on the pharmacokinetics and bioavailability of tacrolimus were investigated in cisplatin-induced renal failure model rats. The bioavailability of tacrolimus was increased by 35% in rats with impaired renal function as compared with normal control. The blood concentration of tacrolimus during intraportal infusion in rats with renal failure showed non-linearity against dose, and was increased as compared with that in normal rats. The intestinal metabolism was not altered, but the absorption rate was significantly increased in the intestine in rats with renal failure. These results suggested that the hepatic metabolism of tacrolimus is impared in rats with renal failure, and that the accelerated absorption rate in the intestine in renal failure is followed by partial saturation of hepatic extraction, which may be one of the mechanisms of increased bioavailability of tacrolimus.