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Three cases of severe hepatic impairment caused by erlotinib.

Lung cancer is the second-most common cancer in men and women, accounting for about 13% of all diagnosed cancers. It is, however, the leading cause of cancer-related deaths in industrialized countries, exceeding the mortality from breast, colorectal, and prostate cancer combined. 
 
Erlotinib is an orally administered, quinazoline-based agent that competes with adenosine triphosphate for binding to the intracellular catalytic domain of the epidermal growth factor receptor (HER1/EGFR) tyrosine kinase, inhibiting phosphorylation. Inhibition of tyrosine kinase activity prevents HER1/EGFR phosphorylation and its associated downstream signaling events, and it may block tumorigenesis that is mediated by inappropriate HER1/EGFR signaling [1]. In November 2004, the U.S. Food and Drug Administration (FDA) approved erlotinib as a single-agent treatment for patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) after failure with at least one standard chemotherapy regimen. 
 
Erlotinib is better tolerated and causes fewer adverse reactions than cytotoxic drugs. The most common adverse reactions in patients are rash (acneform eruptions) and diarrhoea [2]. The majority of hepatotoxicity presents as mild or moderate hepatic dysfunction; severe hepatic impairment has been documented rarely. Here, we report three cases of severe hepatic impairment which was caused by erlotinib. 
 
Erlotinib is cleared predominantly by the liver and is metabolized primarily by oxidation of CYP3A4, which is excreted in bile [3]. CYP3A4 exhibits remarkable interindividual activity as high as 20-fold. Genetic polymorphisms are a common source of these differences in the context of drug metabolism [4]. There are three mutations of CYP3A4 in the Chinese population that have been reported to attenuate CYP3A4 activity. These mutations include A13989G, C15820G and an A17776 insertion [5]. 
 
Additionally, CYP2D6 belongs to the cytochrome P450 oxidase family and is responsible for the majority of the interindividual variability in drug metabolism. There are four phenotypes of CYP2D6: poor metabolizer (PM), intermediate metabolizer (IM), extensive (normal) metabolizer (EM), and ultrarapid metabolizer (UM). If a substrate of the enzyme is given to a patient as medication, and if the patient has impaired CYP2D6, the patient will accumulate the drug and experience severe side effects. In contrast, for the UM patient, drug concentrations might be too low to have a therapeutic effect. Thus, assessing the patient's phenotype will help determine the optimal dose of a drug. 
 
One mutation in the CYP2D6 coding sequence that frequently occurs in the Chinese population is C188T(CYP2D6*10) [6].Therefore, we analyzed DNA samples from two subjects by polymerase chain reaction and direct sequencing of three mutations in the CYP3A4 coding sequence and one mutation in the CYP2D6 coding sequence. Primer design, polymerase chain reaction, and CYP3A4 and CYP2D6 sequencing were performed as described [5, 6].