Polymorphisms ofCYP2D6Gene and Gefitinib-Induced Hepatotoxicity

    loading  Checking for direct PDF access through Ovid

Abstract

Polymorphisms ofCYP2D6were analyzed in 55 patients with non–small-cell lung cancer (NSCLC) who experienced gefitinib-induced hepatotoxicity. Their genotypic distribution was similar to the known distribution in the general Japanese population. However, in patients taking CYP3A4-inhibitory drugs, gefitinib retreatment caused hepatotoxicity more frequently in those withCYP2D6allele*5or*10than in those with normal alleles. Moreover, a switch to erlotinib was not hepatotoxic in all 17 patients with these alleles.

Introduction:

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.

Patients and 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).

Conclusion:

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.

Related Topics

    loading  Loading Related Articles