Drug-induced liver graft toxicity caused by cytochrome P450 poor metabolism.
What is already known about this subject. The activity of drug-metabolizing enzymes, primarily cytochrome P450 enzymes, can determine a patient's response to a drug. Therapeutic failure or drug toxicity in the postoperative period after liver transplantation is influenced by the drug metabolizing capacity of the graft. Dose adjustment or selection of an alternative drug, which is not a substrate for the polymorphic enzyme may prevent the development of side-effects in recipients of poor metabolizer liver grafts. What this study adds. A validated analytical system with metabolomic tools has been developed to estimate the drug-metabolizing capacity of transplanted liver, which allows the prediction of potential poor metabolizer phenotypes of donors and facilitates the improvement of individual recipient therapy. In the test of drug-metabolizing status, one of the liver grafts was found to be a CYP2C9 poor metabolizer, while the other was a CYP2C19 poor metabolizer. Rationalization of the medication resulted in the recovery of both the grafts and the recipients within 1 week.


OBJECTIVE
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.
Kóbori
László
L
Transplantation and Surgical Clinic, Semmelweis University, Baross 23-25, H-1082 Budapest, Hungary.
Kõhalmy
Krisztina
K
Porrogi
Pálma
P
Sárváry
Enikõ
E
Gerlei
Zsuzsa
Z
Fazakas
János
J
Nagy
Péter
P
Járay
Jenõ
J
Monostory
Katalin
K
D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D014644:Genetic Variation / Q000502:physiology; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D016031:Liver Transplantation / Q000009:adverse effects*; D008297:Male; D008875:Middle Aged; D004364:Pharmaceutical Preparations / Q000378:metabolism; D014019:Tissue Donors
D004364:Pharmaceutical Preparations; D003577:Cytochrome P-450 Enzyme System