title: Effects of polymorphisms in CYP2D6 and ABC transporters and side effects induced by gefitinib on the pharmacokinetics of the gefitinib metabolite, O-desmethyl gefitinib.
abstract: We investigated the effects of polymorphisms in CYP2D6, ABCB1, and ABCG2 and the side effects induced by gefitinib on the pharmacokinetics of O-desmethyl gefitinib, the active metabolite of gefitinib. On day 14 after beginning therapy with gefitinib, plasma concentrations of gefitinib and O-desmethyl gefitinib were measured. Patients were grouped into three groups according to their combination of CYP2D6 alleles: homozygous extensive metabolisers (EMs; *1/*1, *1/*2, and *2/*2; n = 13), heterozygous EMs (*1/*5, *2/*5, *1/*10, and *2/*10; n = 18), and intermediate metabolisers (IMs; *5/*10 and *10/*10; n = 5). The median AUC0-24 of O-desmethyl gefitinib in CYP2D6 IMs was 1460 ng h/mL, whereas that in homozygous EMs was 12,523 ng h/mL (P = 0.021 in univariate analysis). The median AUC ratio of O-desmethyl gefitinib to gefitinib differed among homozygous EMs, heterozygous EMs, and IMs at a ratio of 1.41:0.86:0.24 (P = 0.030). On the other hand, there were no significant differences in the AUC0-24 of O-desmethyl gefitinib between ABCB1 and ABCG2 genotypes. In a multivariate analysis, CYP2D6 homozygous EMs (P = 0.012) were predictive for a higher AUC0-24 of O-desmethyl gefitinib. The side effects of diarrhoea, skin rash, and hepatotoxicity induced by gefitinib were unrelated to the AUC0-24 of O-desmethyl gefitinib. CYP2D6 polymorphisms were associated with the formation of O-desmethyl gefitinib from gefitinib. In CYP2D6 homozygous EMs, the plasma concentrations of O-desmethyl gefitinib were higher over 24 h after taking gefitinib than those of the parent compound; however, side effects induced by gefitinib were unrelated to O-desmethyl gefitinib exposure.
authors.affiliation: Department of Pharmacy, Akita University Hospital, 1-1-1 Hondo, Akita, 010-8543, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kobayashi
authors.affiliation: Department of Cardiovascular and Respiratory Medicine, Akita University Graduate School of Medicine, Akita, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Sato
authors.affiliation: Department of Pharmacy, Akita University Hospital, 1-1-1 Hondo, Akita, 010-8543, Japan.
authors.forename: Takenori
authors.initials: T
authors.lastname: Niioka
authors.affiliation: Department of Cardiovascular and Respiratory Medicine, Akita University Graduate School of Medicine, Akita, Japan.
authors.forename: Masahide
authors.initials: M
authors.lastname: Takeda
authors.affiliation: Department of Cardiovascular and Respiratory Medicine, Akita University Graduate School of Medicine, Akita, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Okuda
authors.affiliation: Department of Cardiovascular and Respiratory Medicine, Akita University Graduate School of Medicine, Akita, Japan.
authors.forename: Mariko
authors.initials: M
authors.lastname: Asano
authors.affiliation: Department of Cardiovascular and Respiratory Medicine, Akita University Graduate School of Medicine, Akita, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ito
authors.affiliation: Department of Pharmacy, Akita University Hospital, 1-1-1 Hondo, Akita, 010-8543, Japan. m-miura@hos.akita-u.ac.jp.
authors.forename: Masatomo
authors.initials: M
authors.lastname: Miura
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2 / Q000235:genetics* / Q000378:metabolism; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics* / Q000378:metabolism; D005260:Female; D000077156:Gefitinib; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D008297:Male; D015999:Multivariate Analysis; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D011799:Quinazolines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*
chemical_list: C513055:ABCB1 protein, human; C116614:ABCG2 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; D011799:Quinazolines; D019389:Cytochrome P-450 CYP2D6; D000077156:Gefitinib
keywords: ABC transporter; CYP2D6; Gefitinib; O-Desmethyl gefitinib