Drug-induced liver graft toxicity caused by cytochrome P450 poor metabolism

AIMS The drug-metabolizing capacity of transplanted liver highly influences drug efficacy or toxicity, particularly in the early postoperative period. The aim of our study was to predict therapeutic failures or severe adverse drug reactions by phenotyping for cytochrome P450 (P450) polymorphism resulting in reduced or no activity of the key drug-metabolizing enzymes. METHODS A validated analytical system with metabolomic tools has been developed for estimation of the drug-metabolizing capacity of transplanted liver, which allows the prediction of potential poor metabolizer phenotypes of donors and facilitates improvement of the individual recipient therapy. RESULTS Of the 109 liver donors in Hungary, the frequency of poor metabolizers was found to be 0.92%, 5.5% and 8.3% for CYP2C9, CYP2C19 and CYP2D6, respectively. In the present study, two liver grafts transplanted in paediatric recipients were reported to be poor metabolizer phenotypes. The liver grafts presented normal function in the early postoperative days; 2 weeks after transplantation, however, increasing liver enzymes were detected. Histological investigation of a liver biopsy suggested drug toxicity. The test of drug metabolizing status showed one of the liver grafts to be a CYP2C9 poor metabolizer, and the other was found to be a CYP2C19 poor metabolizer. Rationalization of the medication resulted in the recovery of both the grafts and the recipients within 1 week. CONCLUSIONS Prospective investigation of the P450 status may lead to the optimization of drug choice and/or dose for a more effective therapy, avoid serious adverse effects, and decrease medical costs. Phenotyping donor livers and tailored medication can contribute to the improvement of graft and recipient survival.