{"title":"CYP2C9和CYP2C19基因多态性对格列齐特在健康人体内药代动力学和药效学的影响","authors":"Pureum Kang, Chang-Keun Cho, Choon-Gon Jang, Seok-Yong Lee, Yun Jeong Lee, Chang-Ik Choi, Jung-Woo Bae","doi":"10.1007/s12272-023-01448-z","DOIUrl":null,"url":null,"abstract":"<div><p>Gliclazide metabolism is mediated by genetically polymorphic CYP2C9 and CYP2C19 enzymes. We investigated the effects of <i>CYP2C9</i> and <i>CYP2C19</i> genetic polymorphisms on the pharmacokinetics and pharmacodynamics of gliclazide. Twenty-seven Korean healthy volunteers were administered a single oral dose of gliclazide 80 mg. The plasma concentration of gliclazide was quantified for the pharmacokinetic analysis and plasma concentrations of glucose and insulin were measured as pharmacodynamic parameters. The pharmacokinetics of gliclazide showed a significant difference according to the number of defective alleles of combined <i>CYP2C9</i> and <i>CYP2C19</i>. The two defective alleles group (group 3) and one defective allele group (group 2) showed 2.34- and 1.46-fold higher AUC<sub>0–∞</sub> (<i>P</i> < 0.001), and 57.1 and 32.3% lower CL/F (<i>P</i> < 0.001), compared to those of the no defective allele group (group 1), respectively. The <i>CYP2C9IM–</i><i>CYP2C19IM</i> group had AUC<sub>0–∞</sub> increase of 1.49-fold (<i>P</i> < 0.05) and CL/F decrease by 29.9% (<i>P</i> < 0.01), compared with the <i>CYP2C9 Normal Metabolizer</i> (<i>CYP2C9NM</i>)–<i>CYP2C19IM</i> group. The <i>CYP2C9NM–CYP2C19PM</i> group and <i>CYP2C9NM–CYP2C19IM</i> group showed 2.41- and 1.51-fold higher AUC<sub>0–∞</sub> (<i>P</i> < 0.001), and 59.6 and 35.4% lower CL/F (<i>P</i> < 0.001), compared to those of the <i>CYP2C9NM–CYP2C19NM</i> group, respectively. The results represented that <i>CYP2C9</i> and <i>CYP2C19</i> genetic polymorphisms significantly affected the pharmacokinetics of gliclazide. Although the genetic polymorphism of <i>CYP2C19</i> had a greater effect on the pharmacokinetics of gliclazide, the genetic polymorphism of <i>CYP2C9</i> also had a significant effect. On the other hand, plasma glucose and insulin responses to gliclazide were not significantly affected by the <i>CYP2C9–CYP2C19</i> genotypes, requiring further well-controlled studies with long-term dosing of gliclazide in diabetic patients.\n</p></div>","PeriodicalId":8287,"journal":{"name":"Archives of Pharmacal Research","volume":"46 5","pages":"438 - 447"},"PeriodicalIF":6.9000,"publicationDate":"2023-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s12272-023-01448-z.pdf","citationCount":"1","resultStr":"{\"title\":\"Effects of CYP2C9 and CYP2C19 genetic polymorphisms on the pharmacokinetics and pharmacodynamics of gliclazide in healthy subjects\",\"authors\":\"Pureum Kang, Chang-Keun Cho, Choon-Gon Jang, Seok-Yong Lee, Yun Jeong Lee, Chang-Ik Choi, Jung-Woo Bae\",\"doi\":\"10.1007/s12272-023-01448-z\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><p>Gliclazide metabolism is mediated by genetically polymorphic CYP2C9 and CYP2C19 enzymes. We investigated the effects of <i>CYP2C9</i> and <i>CYP2C19</i> genetic polymorphisms on the pharmacokinetics and pharmacodynamics of gliclazide. Twenty-seven Korean healthy volunteers were administered a single oral dose of gliclazide 80 mg. The plasma concentration of gliclazide was quantified for the pharmacokinetic analysis and plasma concentrations of glucose and insulin were measured as pharmacodynamic parameters. The pharmacokinetics of gliclazide showed a significant difference according to the number of defective alleles of combined <i>CYP2C9</i> and <i>CYP2C19</i>. The two defective alleles group (group 3) and one defective allele group (group 2) showed 2.34- and 1.46-fold higher AUC<sub>0–∞</sub> (<i>P</i> < 0.001), and 57.1 and 32.3% lower CL/F (<i>P</i> < 0.001), compared to those of the no defective allele group (group 1), respectively. The <i>CYP2C9IM–</i><i>CYP2C19IM</i> group had AUC<sub>0–∞</sub> increase of 1.49-fold (<i>P</i> < 0.05) and CL/F decrease by 29.9% (<i>P</i> < 0.01), compared with the <i>CYP2C9 Normal Metabolizer</i> (<i>CYP2C9NM</i>)–<i>CYP2C19IM</i> group. The <i>CYP2C9NM–CYP2C19PM</i> group and <i>CYP2C9NM–CYP2C19IM</i> group showed 2.41- and 1.51-fold higher AUC<sub>0–∞</sub> (<i>P</i> < 0.001), and 59.6 and 35.4% lower CL/F (<i>P</i> < 0.001), compared to those of the <i>CYP2C9NM–CYP2C19NM</i> group, respectively. The results represented that <i>CYP2C9</i> and <i>CYP2C19</i> genetic polymorphisms significantly affected the pharmacokinetics of gliclazide. Although the genetic polymorphism of <i>CYP2C19</i> had a greater effect on the pharmacokinetics of gliclazide, the genetic polymorphism of <i>CYP2C9</i> also had a significant effect. On the other hand, plasma glucose and insulin responses to gliclazide were not significantly affected by the <i>CYP2C9–CYP2C19</i> genotypes, requiring further well-controlled studies with long-term dosing of gliclazide in diabetic patients.\\n</p></div>\",\"PeriodicalId\":8287,\"journal\":{\"name\":\"Archives of Pharmacal Research\",\"volume\":\"46 5\",\"pages\":\"438 - 447\"},\"PeriodicalIF\":6.9000,\"publicationDate\":\"2023-04-25\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://link.springer.com/content/pdf/10.1007/s12272-023-01448-z.pdf\",\"citationCount\":\"1\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Archives of Pharmacal Research\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://link.springer.com/article/10.1007/s12272-023-01448-z\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CHEMISTRY, MEDICINAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Archives of Pharmacal Research","FirstCategoryId":"3","ListUrlMain":"https://link.springer.com/article/10.1007/s12272-023-01448-z","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
Effects of CYP2C9 and CYP2C19 genetic polymorphisms on the pharmacokinetics and pharmacodynamics of gliclazide in healthy subjects
Gliclazide metabolism is mediated by genetically polymorphic CYP2C9 and CYP2C19 enzymes. We investigated the effects of CYP2C9 and CYP2C19 genetic polymorphisms on the pharmacokinetics and pharmacodynamics of gliclazide. Twenty-seven Korean healthy volunteers were administered a single oral dose of gliclazide 80 mg. The plasma concentration of gliclazide was quantified for the pharmacokinetic analysis and plasma concentrations of glucose and insulin were measured as pharmacodynamic parameters. The pharmacokinetics of gliclazide showed a significant difference according to the number of defective alleles of combined CYP2C9 and CYP2C19. The two defective alleles group (group 3) and one defective allele group (group 2) showed 2.34- and 1.46-fold higher AUC0–∞ (P < 0.001), and 57.1 and 32.3% lower CL/F (P < 0.001), compared to those of the no defective allele group (group 1), respectively. The CYP2C9IM–CYP2C19IM group had AUC0–∞ increase of 1.49-fold (P < 0.05) and CL/F decrease by 29.9% (P < 0.01), compared with the CYP2C9 Normal Metabolizer (CYP2C9NM)–CYP2C19IM group. The CYP2C9NM–CYP2C19PM group and CYP2C9NM–CYP2C19IM group showed 2.41- and 1.51-fold higher AUC0–∞ (P < 0.001), and 59.6 and 35.4% lower CL/F (P < 0.001), compared to those of the CYP2C9NM–CYP2C19NM group, respectively. The results represented that CYP2C9 and CYP2C19 genetic polymorphisms significantly affected the pharmacokinetics of gliclazide. Although the genetic polymorphism of CYP2C19 had a greater effect on the pharmacokinetics of gliclazide, the genetic polymorphism of CYP2C9 also had a significant effect. On the other hand, plasma glucose and insulin responses to gliclazide were not significantly affected by the CYP2C9–CYP2C19 genotypes, requiring further well-controlled studies with long-term dosing of gliclazide in diabetic patients.
期刊介绍:
Archives of Pharmacal Research is the official journal of the Pharmaceutical Society of Korea and has been published since 1976. Archives of Pharmacal Research is an interdisciplinary journal devoted to the publication of original scientific research papers and reviews in the fields of drug discovery, drug development, and drug actions with a view to providing fundamental and novel information on drugs and drug candidates.