Liver transplantation protein metabolism

The plasma protein binding of tacrolimus is approximately 99%. Tacrolimus is bound mainly to albumin and alpha-1-acid glycoprotein and has a high level of association with erythrocytes. It is extensively metabolized by the mixed-function oxidase system, primarily the cytochrome P450 system (CYP3A). The disposition of tacrolimus from whole blood was biphasic with a terminal elimination half-life of 11.7 hours in liver transplant patients. 

Treatment involves a low-protein diet (0.5-0.7 g/kg BW/day) with a sufficient supply of calories. Substitution of essential amino acids (in about the same quantity) is required. The administration of benzoate (0.1-0.25 g/kg BW/day), arginine hydrochloride (1 mmol/kg BW/day) or sodium phenylacetate (0.3-0.5 g/ kg BW/day) (phenylbutyrate tends to be more effective) facilitates nitrogen excretion via other metabolic pathways. (168-170) With an enhanced excretion of orotate or other metabolites of pyrimidine synthesis, the administration of allopurinol leads to an increase in the excretion of nitrogen via metabolites from pyrimidine synthesis. Ammonia and urea precursors are eliminated by haemodialysis. In individual cases, liver transplantation is indicated. (I7l)... 

Tacrolimus is given orally (twice-daily dose regimen) or as an injection. A modified release (MR) oral dosage form of tacrolimus has been developed for administration once a day to overcome noncompliance, which is the major problem in acute graft rejection in solid transplant recipients. Tacrolimus is not completely absorbed by the GI tract and its rate of absorption could vary. It binds to plasma protein at a rate of 75-99% with a half-life of approximately 12 h and is predominantly metabolized in liver by CYP3A. Some of its metabolites have immunosuppressive activity. Most of the tacrolimus is excreted in feces, and a negligible amount (< 1%) is excreted in urine without undergoing any metabolism. 

Another group of experimentors tried to study the preferential utilisation of intact proteins or partial hydrolysates by means of the metabolic trap technique, which consists in measuring the effectiveness with which a labeled free amino acid can compete with larger protein fragments in the formation of new protein. The most positive evidence for the direct utilisation of such fn ments was generally found with embryonic and tumor tissues. Thus Ebert (343) found that when transplants of chick embryo kidney, liver, or spleen, labeled with S -methionine, were made into chick embryos, the radioactivity appeared predominantly in the correspondit organ, and that this transfer of radioactivity could not be inhibited by free methionine. Similarly, Francis and Winnick (344) found that the soluble proteins of a chick embryo extract were utilized in preference to free amino acids by embryonic heart cultures and that, furthermore, p-fluorophenyl-alanine did not inhibit the transfer of phenylalanine from the embryo extract proteins. These experiments, however, are open to many interpretations, especially since functional adoption (or merely adsorption) of the exogenous proteins by the different tissues has not been excluded. 

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