Determinants of gefitinib pharmacokinetics in healthy Chinese male subjects: A pharmacogenomic study of cytochrome p450 enzymes and transporters.
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 tra...
| Publicado en: | Journal of Clinical Pharmacy & Therapeutics Vol. 45; no. 5; pp. 1159 - 1168 |
|---|---|
| Autores principales: | , , , , , , , , , |
| Formato: | research tables/charts Journal Article |
| Publicado: |
Wiley-Blackwell
Oct2020
|
| Acceso en línea: | Ver este registro en EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=145624936&site=ehost-live header: @attributes: shortDbName: ccm uiTerm: 145624936 longDbName: CINAHL Complete uiTag: AN controlInfo: bkinfo: dissinfo: jinfo: jid: 02694727 EV4 jtl: Journal of Clinical Pharmacy & Therapeutics issn: 02694727 maglogo: Y pubinfo: dt: Oct2020 vid: 45 iid: 5 pid: 480 pub: Wiley-Blackwell place: Malden, Massachusetts artinfo: ui: 145624936 145624936 145837359 145624936 10.1111/jcpt.13168 145624936 ppf: 1159 ppct: 9 formats: fmt: – @attributes: type: T – @attributes: type: C – @attributes: type: P tig: atl: Determinants of gefitinib pharmacokinetics in healthy Chinese male subjects: A pharmacogenomic study of cytochrome p450 enzymes and transporters. aug: au: Wan, Zirui Guo, Lifang Li, Pengfei Zhao, Zhixia Xu, Benshan Ren, Lulu Yan, Yan Liu, He Zhang, Yiwen Liu, Lihong affil: Pharmacy Department of Beijing Chao‐Yang Hospital, Capital Medical University, Beijing, China sug: subj: Gefitinib Pharmacokinetics Pharmacogenetics Polymorphism, Single Nucleotide Cytochrome P-450 Enzyme System Metabolism Carrier Proteins Metabolism Men's Health Chinese Persons Human Sequence Analysis Chromatography, Liquid Mass Spectrometry Unpaired T-Tests Mann-Whitney U Test Step-Wise Multiple Regression Multiple Linear Regression Tyrosine Kinase Inhibitors Alleles Descriptive Statistics ab: 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. pubtype: Academic Journal doctype: research tables/charts Journal Article ougenre: Article language: English refInfo: holdings: @attributes: islocal: N |
|---|