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Effects of polymorphisms in CYP2D6 and ABC transporters and side effects induced by gefitinib on the pharmacokinetics of the gefitinib metabolite, O-desmethyl gefitinib

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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.

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Abbreviations

ABC:

ATP-binding cassette

AUC:

Area under the observed plasma concentration–time curve

BCRP:

Breast cancer resistance protein

CYP:

Cytochrome P450

EGFR:

Epidermal growth factor receptor

EMs:

Extensive metabolisers

HPLC:

High-performance liquid chromatography

IMs:

Intermediate metabolisers

NSCLC:

Non-small cell lung cancer

SNP:

Single nucleotide polymorphism

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Acknowledgments

This work was supported by grants (Nos. 23590168 and 26460188) from the Japan Society for the Promotion of Science, Tokyo, Japan.

Authors’ contributions

HK, KS, HI, and MM participated in the design of the study and reviewed the results. KS, MT, YO, MA, and HI were responsible for the patient collection and involved in acquisition of data. HK carried out genotyping. MM analysed plasma concentrations. HK, TN, and MM were responsible for the statistical analysis. HK and MM drafted the manuscript. KS, KS, MT, YO, MA, and HI helped to draft the manuscript. All authors read and approved the final manuscript.

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Authors and Affiliations

  1. Department of Pharmacy, Akita University Hospital, 1-1-1 Hondo, Akita, 010-8543, Japan

    Hiroyuki Kobayashi, Takenori Niioka & Masatomo Miura

  2. Department of Cardiovascular and Respiratory Medicine, Akita University Graduate School of Medicine, Akita, Japan

    Kazuhiro Sato, Masahide Takeda, Yuji Okuda, Mariko Asano & Hiroshi Ito

Authors
  1. Hiroyuki Kobayashi
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  2. Kazuhiro Sato
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  3. Takenori Niioka
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  4. Masahide Takeda
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  6. Mariko Asano
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  7. Hiroshi Ito
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  8. Masatomo Miura
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Correspondence to Masatomo Miura.

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Kobayashi, H., Sato, K., Niioka, T. et al. Effects of polymorphisms in CYP2D6 and ABC transporters and side effects induced by gefitinib on the pharmacokinetics of the gefitinib metabolite, O-desmethyl gefitinib. Med Oncol 33, 57 (2016). https://doi.org/10.1007/s12032-016-0773-5

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