Impact of Q141K on the Transport of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors by ABCG2
Yutaka Inoue,
Takashi Morita,
Mari Onozuka,
Ken-ichi Saito,
Kazumi Sano,
Kazuhiko Hanada,
Masami Kondo,
Yoichi Nakamura,
Tohru Kishino,
Hiroshi Nakagawa,
Yoji Ikegami
Affiliations
Yutaka Inoue
Department of Phrmacometrics and Pharmacokinetics, Meiji Pharmaceutical University, 2-522-1 Noshio Kiyose-shi, Tokyo 204-8588, Japan
Takashi Morita
Department of Phrmacometrics and Pharmacokinetics, Meiji Pharmaceutical University, 2-522-1 Noshio Kiyose-shi, Tokyo 204-8588, Japan
Mari Onozuka
Department of Phrmacometrics and Pharmacokinetics, Meiji Pharmaceutical University, 2-522-1 Noshio Kiyose-shi, Tokyo 204-8588, Japan
Ken-ichi Saito
Department of Phrmacometrics and Pharmacokinetics, Meiji Pharmaceutical University, 2-522-1 Noshio Kiyose-shi, Tokyo 204-8588, Japan
Kazumi Sano
Department of Phrmacometrics and Pharmacokinetics, Meiji Pharmaceutical University, 2-522-1 Noshio Kiyose-shi, Tokyo 204-8588, Japan
Kazuhiko Hanada
Department of Phrmacometrics and Pharmacokinetics, Meiji Pharmaceutical University, 2-522-1 Noshio Kiyose-shi, Tokyo 204-8588, Japan
Masami Kondo
Department of Pharmacy Services, Saitama Medical Center, Saitama Medical University, 1981 Kamoda, Kawagoe-shi, Saitama 350-8550, Japan
Yoichi Nakamura
Department of Medical Oncology, Division of Thoracic Oncology, Tochigi Cancer Center, 4-9-13 Yohnan Utsunomiya-shi, Tochigi 320-0834, Japan
Tohru Kishino
Department of Pharmacy Services, Saitama Medical University Hospital, 38 Morohongo, Moroyama-machi, Iruma-gun, Saitama 350-0495, Japan
Hiroshi Nakagawa
Department of Applied Biological Chemistry, Graduate School of Bioscience and Biotechnology, Chubu University, 1200 Matsumoto-cho, Kasugai-shi, Aichi 487-8501, Japan
Yoji Ikegami
Department of Phrmacometrics and Pharmacokinetics, Meiji Pharmaceutical University, 2-522-1 Noshio Kiyose-shi, Tokyo 204-8588, Japan
The ATP-binding cassette transporter ABCG2 is expressed in various organs, such as the small intestine, liver, and kidney, and influences the pharmacokinetics of drugs that are its substrates. ABCG2 is also expressed by cancer cells and mediates resistance to anticancer agents by promoting the efflux of these drugs. In the present study, we investigated the interactions between epidermal growth factor receptor tyrosine kinase inhibitors and ABCG2 by MTT assay, intracellular drug accumulation assay, and FACS. This study showed that four epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) (gefitinib, erlotinib, lapatinib, and afatinib) were transported from tumor cells as substrates of ABCG2. Q141K is a common single-nucleotide polymorphism of ABCG2 in Asians. We demonstrated that the extracellular efflux of gefitinib, erlotinib, and lapatinib was reduced by Q141K, whereas afatinib transport was not affected. In addition, all four EGFR TKIs inhibited the transport of other substrates by both wild-type and variant ABCG2 at 0.1 μM concentrations. Accordingly, epidermal growth factor receptor tyrosine kinase inhibitors may induce interactions with other drugs that are substrates of ABCG2, and single-nucleotide polymorphisms of ABCG2 may influence both the pharmacokinetics and efficacy of these anticancer agents.
