Formation of reactive metabolites and management of tyrosine kinase inhibitor-induced hepatotoxicity: a literature review.
BACKGROUND
Existing clinical evidence indicates that many tyrosine kinase inhibitors (TKIs) are associated with idiosyncratic hepatotoxicity. TKIs possess risk factors for developing drug-induced liver injury such as their high daily dose, being substrates of P450 enzyme and being involved in significant hepatic metabolism. Several successful strategies to overcome TKI-induced hepatotoxicity include: switching to an alternative TKI with a similar mechanism of action, using an alternative dose and introduction of corticosteroids for treatment and prevention of hepatotoxicity.


METHODS
This review highlights the formation of reactive metabolites and how this leads to toxicity, as well as the current clinical management of TKI-induced hepatotoxicity.


CONCLUSIONS
Numerous events need to occur in an individual patient before converging into an idiosyncratic hepatotoxicity episode. Of these, the formation of a reactive intermediate through metabolism appears to be the prerequisite. This critical event involves an intricate chemico-biological interaction where, on one hand, drug-specific characteristics create the propensity for occurrence and, on the other hand, patient risk factors determine the individuality of response. With improved understanding of the mechanisms leading to adverse events, several strategies are being adopted to prevent and treat TKI-induced hepatotoxicity. However, further evidence is required before they can be recommended to larger populations.
National University of Singapore, Department of Pharmacy, Faculty of Science , 18 Science Drive 4, Singapore 117543 , Singapore +65 6516 7814, +65 6516 7963 ; +65 6779 1554 ; phaac@nus.edu.sg , phahohk@nus.edu.sg.
Yi Ling
YL
Teo
Han Kiat
HK
Ho
Alexandre
A
Chan
D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000517:prevention & control / Q000628:therapy*; D004305:Dose-Response Relationship, Drug; D005938:Glucocorticoids / Q000627:therapeutic use; D006801:Humans; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects* / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D012307:Risk Factors
D005938:Glucocorticoids; D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases
hepatotoxicity; management; reactive metabolites; tyrosine kinase inhibitors