title: Polymorphisms of CYP2D6 gene and gefitinib-induced hepatotoxicity.
abstract: BACKGROUND
  Gefitinib induces severe hepatotoxicity in approximately a quarter of Japanese patients with epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer (NSCLC). Gefitinib is metabolized by cytochrome P450 (CYP) enzymes--including CYP3A4/5, CYP1A1, and CYP2D6--in the liver. We hypothesized that polymorphisms of the CYP2D6 gene may account for gefitinib-induced hepatotoxicity.
  
  
  METHODS
  Polymorphisms of the CYP2D6 gene were analyzed in 55 patients with NSCLC who experienced grade ≥ 2 transaminase elevation from gefitinib. The distribution of the CYP2D6 genotype was compared with that of the healthy Japanese population. The correlations between the nonfunctional allele *5 or the reduced-function allele *10 and hepatotoxicity-related clinical factors were also examined.
  
  
  RESULTS
  The distribution of the CYP2D6 genotype in the study participants was not different from that of the general Japanese population, reported previously. Existence of allele *5 or *10 did not correlate with clinical factors such as onset of hepatotoxicity within 2 months, grade ≥ 3 serum transaminase elevation, and tolerability to dose reduction or rechallenge of gefitinib. However, in 7 patients taking CYP3A4-inhibitory drugs, rechallenge of gefitinib again caused hepatotoxicity in 4 patients with allele *5 or *10 but not in 3 patients with normal alleles (P = .029). Moreover, switching to erlotinib did not cause hepatotoxicity in any of 17 patients with allele *5 or *10 but did in 3 of 8 patients without these alleles (P = .024).
  
  
  CONCLUSIONS
  Reduced function of CYP2D6 may partly account for gefitinib-induced hepatotoxicity when CYP3A4 is inhibited. Erlotinib could be safely used in patients with decreased CYP2D6 activity even after they experienced gefitinib-induced hepatotoxicity.
authors.affiliation: Department of Internal Medicine, Toyonaka Municipal Hospital, Osaka, Japan. tkijima@imed3.med.osaka-u.ac.jp
authors.forename: Takayuki
authors.initials: T
authors.lastname: Takimoto
authors.forename: Takashi
authors.initials: T
authors.lastname: Kijima
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Otani
authors.forename: Shinpei
authors.initials: S
authors.lastname: Nonen
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Namba
authors.forename: Masahide
authors.initials: M
authors.lastname: Mori
authors.forename: Soichiro
authors.initials: S
authors.lastname: Yokota
authors.forename: Seigo
authors.initials: S
authors.lastname: Minami
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Komuta
authors.forename: Junji
authors.initials: J
authors.lastname: Uchida
authors.forename: Fumio
authors.initials: F
authors.lastname: Imamura
authors.forename: Mitsugi
authors.initials: M
authors.lastname: Furukawa
authors.forename: Naotoshi
authors.initials: N
authors.lastname: Tsuruta
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Fujio
authors.forename: Junichi
authors.initials: J
authors.lastname: Azuma
authors.forename: Isao
authors.initials: I
authors.lastname: Tachibana
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kumanogoh
mesh_terms: D000230:Adenocarcinoma / Q000150:complications / Q000235:genetics / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002289:Carcinoma, Non-Small-Cell Lung / Q000150:complications / Q000235:genetics* / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000150:complications / Q000235:genetics / Q000473:pathology; D016022:Case-Control Studies; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D000077156:Gefitinib; D006801:Humans; D008107:Liver Diseases / Q000175:diagnosis / Q000209:etiology*; D008175:Lung Neoplasms / Q000150:complications / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D011110:Polymorphism, Genetic / Q000235:genetics*; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000009:adverse effects*; D011799:Quinazolines / Q000009:adverse effects*
chemical_list: D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D019389:Cytochrome P-450 CYP2D6; D000077156:Gefitinib
keywords: CYP2D6; Erlotinib; Gefitinib; Hepatotoxicity; Polymorphisms