Ophthalmic acid in plasma: A possible predictor for elevated risk of erlotinib-induced hepatotoxicity.

Abstract

e13072 Background: Erlotinib is metabolized by cytochrome P450 enzymes to form a para-hydroxyaniline metabolite that is further metabolized to quinone-imine. Erlotinib is detoxified when it conjugates with sulfate or glucuronide. We recently demonstrated that patients who experienced severe erlotinib-induced hepatotoxicity had higher metabolic ratios of glucuronides than those who developed moderate toxicity; this finding indicates that glucuronidation could be saturated and high levels of reactive metabolites might be trigger of glutathione (GSH) depletion. Ophthalmic acid (OA), which is an analog of GSH, may be a useful biomarker for hepatotoxicity because it is a sensitive indicator of GSH depletion in animal model. GSH acts as an enzyme-catalyzed antioxidant when cells and organisms experience electrophilic stress that arises from metabolic processes. Here, we examined the association between plasma concentration of OA and hepatotoxicity in patients who were treated with erlotinib in Japanese patients. Methods: We assessed data from 26 patients with NSCLC who each received a 150 mg dose of erlotinib. Plasma concentrations of OA and erlotinib were measured at before treatment using the liquid chromatography-quadrupole mass spectrometer system. Results: All 26 patients experienced one or more erlotinib-induced adverse events. The most frequent erlotinib-induced adverse events were mild to moderate skin rashes and diarrhea. There seemed to be a relationship between the plasma concentration of erlotinib and the grades of skin rashes and diarrhea. Interestingly, OA was detected only in one patient who developed grade 4 hepatotoxicity, indicating that this patient, who had a higher level of OA (36.9 ng/mL) in plasma. In contrast, the other 25 patients, who did not develop hepatotoxicity, had no detectable OA in plasma. Thus, the plasma concentration of OA was not related to the plasma concentration of erlotinib nor to the grade of skin rash. Conclusions: OA might be useful as a predictive biomarker of hepatotoxicity if measured before starting erlotinib treatment. Larger studies are needed to investigate the association between OA levels and the development of severe hepatotoxicity.