Determinants of gefitinib pharmacokinetics in healthy Chinese male subjects: A pharmacogenomic study of cytochrome p450 enzymes and transporters

Journal of Clinical Pharmacy and TherapeuticsVolume 45, Issue 5 p. 1159-1167 ORIGINAL ARTICLE Determinants of gefitinib pharmacokinetics in healthy Chinese male subjects: A pharmacogenomic study of cytochrome p450 enzymes and transporters Zirui Wan MA, Corresponding Author maxim_w@163.com Pharmacy Department of Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China Correspondence Zirui Wan and Lihong Liu, Pharmacy Department of Beijing Chao-Yang Hospital, Capital Medical University, No.8 Gongren Tiyuchang Nanlu, Chaoyang District, Beijing, China. Emails: maxim_w@163.com (Z.W.); liulihong@bjcyh.com (L.L.) Yiwen Zhang, Department of Pharmacy, People's Hospital of Hangzhou Medical College, Zhejiang Provincial People's Hospital, 158 Shangtang Road, Hangzhou, 310014 Zhejiang, China. Email: zjzyw2003@163.comSearch for more papers by this authorLifang Guo PhD, orcid.org/0000-0002-6935-0928 Pharmacy Department of Beijing Chao-Yang Hospital, Capital Medical University, Beijing, ChinaSearch for more papers by this authorPengfei Li MA, Pharmacy Department of Beijing Chao-Yang Hospital, Capital Medical University, Beijing, ChinaSearch for more papers by this authorZhixia Zhao MA, Pharmacy Department of Beijing Chao-Yang Hospital, Capital Medical University, Beijing, ChinaSearch for more papers by this authorBenshan Xu MA, Pharmacy Department of Beijing Chao-Yang Hospital, Capital Medical University, Beijing, ChinaSearch for more papers by this authorLulu Ren MA, Pharmacy Department of Beijing Chao-Yang Hospital, Capital Medical University, Beijing, ChinaSearch for more papers by this authorYan Yan MA, Pharmacy Department of Beijing Chao-Yang Hospital, Capital Medical University, Beijing, ChinaSearch for more papers by this authorHe Liu PhD, Pharmacy Department of Beijing Chao-Yang Hospital, Capital Medical University, Beijing, ChinaSearch for more papers by this authorYiwen Zhang PhD, Corresponding Author zjzyw2003@163.com Department of Pharmacy, People's Hospital of Hangzhou Medical College, Zhejiang Provincial People's Hospital, Hangzhou, China Correspondence Zirui Wan and Lihong Liu, Pharmacy Department of Beijing Chao-Yang Hospital, Capital Medical University, No.8 Gongren Tiyuchang Nanlu, Chaoyang District, Beijing, China. Emails: maxim_w@163.com (Z.W.); liulihong@bjcyh.com (L.L.) Yiwen Zhang, Department of Pharmacy, People's Hospital of Hangzhou Medical College, Zhejiang Provincial People's Hospital, 158 Shangtang Road, Hangzhou, 310014 Zhejiang, China. Email: zjzyw2003@163.comSearch for more papers by this authorLihong Liu PhD, Corresponding Author liulihong@bjcyh.com Pharmacy Department of Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China Correspondence Zirui Wan and Lihong Liu, Pharmacy Department of Beijing Chao-Yang Hospital, Capital Medical University, No.8 Gongren Tiyuchang Nanlu, Chaoyang District, Beijing, China. Emails: maxim_w@163.com (Z.W.); liulihong@bjcyh.com (L.L.) Yiwen Zhang, Department of Pharmacy, People's Hospital of Hangzhou Medical College, Zhejiang Provincial People's Hospital, 158 Shangtang Road, Hangzhou, 310014 Zhejiang, China. Email: zjzyw2003@163.comSearch for more papers by this author Zirui Wan MA, Corresponding Author maxim_w@163.com Pharmacy Department of Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China Correspondence Zirui Wan and Lihong Liu, Pharmacy Department of Beijing Chao-Yang Hospital, Capital Medical University, No.8 Gongren Tiyuchang Nanlu, Chaoyang District, Beijing, China. Emails: maxim_w@163.com (Z.W.); liulihong@bjcyh.com (L.L.) Yiwen Zhang, Department of Pharmacy, People's Hospital of Hangzhou Medical College, Zhejiang Provincial People's Hospital, 158 Shangtang Road, Hangzhou, 310014 Zhejiang, China. Email: zjzyw2003@163.comSearch for more papers by this authorLifang Guo PhD, orcid.org/0000-0002-6935-0928 Pharmacy Department of Beijing Chao-Yang Hospital, Capital Medical University, Beijing, ChinaSearch for more papers by this authorPengfei Li MA, Pharmacy Department of Beijing Chao-Yang Hospital, Capital Medical University, Beijing, ChinaSearch for more papers by this authorZhixia Zhao MA, Pharmacy Department of Beijing Chao-Yang Hospital, Capital Medical University, Beijing, ChinaSearch for more papers by this authorBenshan Xu MA, Pharmacy Department of Beijing Chao-Yang Hospital, Capital Medical University, Beijing, ChinaSearch for more papers by this authorLulu Ren MA, Pharmacy Department of Beijing Chao-Yang Hospital, Capital Medical University, Beijing, ChinaSearch for more papers by this authorYan Yan MA, Pharmacy Department of Beijing Chao-Yang Hospital, Capital Medical University, Beijing, ChinaSearch for more papers by this authorHe Liu PhD, Pharmacy Department of Beijing Chao-Yang Hospital, Capital Medical University, Beijing, ChinaSearch for more papers by this authorYiwen Zhang PhD, Corresponding Author zjzyw2003@163.com Department of Pharmacy, People's Hospital of Hangzhou Medical College, Zhejiang Provincial People's Hospital, Hangzhou, China Correspondence Zirui Wan and Lihong Liu, Pharmacy Department of Beijing Chao-Yang Hospital, Capital Medical University, No.8 Gongren Tiyuchang Nanlu, Chaoyang District, Beijing, China. Emails: maxim_w@163.com (Z.W.); liulihong@bjcyh.com (L.L.) Yiwen Zhang, Department of Pharmacy, People's Hospital of Hangzhou Medical College, Zhejiang Provincial People's Hospital, 158 Shangtang Road, Hangzhou, 310014 Zhejiang, China. Email: zjzyw2003@163.comSearch for more papers by this authorLihong Liu PhD, Corresponding Author liulihong@bjcyh.com Pharmacy Department of Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China Correspondence Zirui Wan and Lihong Liu, Pharmacy Department of Beijing Chao-Yang Hospital, Capital Medical University, No.8 Gongren Tiyuchang Nanlu, Chaoyang District, Beijing, China. Emails: maxim_w@163.com (Z.W.); liulihong@bjcyh.com (L.L.) Yiwen Zhang, Department of Pharmacy, People's Hospital of Hangzhou Medical College, Zhejiang Provincial People's Hospital, 158 Shangtang Road, Hangzhou, 310014 Zhejiang, China. Email: zjzyw2003@163.comSearch for more papers by this author First published: 20 June 2020 https://doi.org/10.1111/jcpt.13168Citations: 2 Zirui Wan, Lifang Guo and Pengfei Li contributed equally to this work. Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinked InRedditWechat Abstract What is known and objective Gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, exhibited a wide interindividual variability in pharmacokinetics. In the present study, we aimed to evaluate the impact of single-nucleotide polymorphisms in the metabolizing enzymes and transporters on gefitinib disposition in healthy Chinese subjects. Methods Fourteen single-nucleotide polymorphisms, including polymorphisms of ATP-binding cassette (ABC) transporters and cytochrome P450 enzymes, were genotyped by Sanger sequencing, and the concentration of gefitinib was measured by ultrafast liquid chromatography-tandem mass spectrometry. The association between the pharmacokinetic parameters (peak plasma concentration [Cmax], time to reach Cmax, plasma half-life, area under the concentration-time curve from 0 to 168 hours [AUC(0-168h)], AUC(0-∞) and plasma clearance [CL/F]) and genotypes was evaluated using unpaired t test or Mann-Whitney U test. A stepwise multiple linear regression analysis was applied to assess the relationships between multiple factors and gefitinib pharmacokinetics. Thirty-nine healthy Chinese male subjects were enrolled in the pharmacokinetic study. Results and discussion Subjects carrying an ABCG2 A allele (c.421CA + c.421AA genotypes) exhibited 33 and 37% increases in the mean gefitinib AUC(0-168h) and AUC(0-∞) values (P < .05), respectively, compared to that of subjects carrying wild-type ABCG2 (c.421CC). Additionally, the mean CL/F of the c.421A allele carriers was 32% less than that of the c.421CC carriers (P < .05). No associations were found between polymorphisms in other metabolic enzymes or ABC transporters and gefitinib pharmacokinetics. What is new and conclusion Our results suggested that a single-nucleotide polymorphism in ABCG2 (c.421C>A) significantly affected the pharmacokinetics of gefitinib. Further studies are required to evaluate the effects of single-nucleotide polymorphism on the pharmacokinetics, pharmacodynamics and toxicity of gefitinib. Citing Literature Supporting Information Filename Description jcpt13168-sup-0001-TableS1.docWord document, 55.5 KB Table S1 Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. Volume45, Issue5October 2020Pages 1159-1167 RelatedInformation