{"title":"Chebulinic Acid的临床前药代动力学和CYP调节活性：一种对抗代谢性疾病的有效分子。","authors":"Arpon Biswas, Sarvesh Kumar Verma, Shiv Kumar, Tripti Mishra, Mukesh Kumar, Abhijit Deb Choudhury, Sristi Agrawal, Sachin Nashik Sanap, Amol Chhatrapati Bisen, Anjali Mishra, Tadigoppula Narender, Rabi Sankar Bhatta","doi":"10.2174/1389200224666230817101950","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Chebulinic acid (CA) is an active constituent of <i>Terminalia chebula</i> fruits with therapeutic potential against multiple metabolic diseases, including dementia, benign prostate hyperplasia, and osteoporosis.</p><p><strong>Objective: </strong>The present work intends to explore the preclinical pharmacokinetics, including the absolute bioavailability of CA and its influence on the gene expression of cytochrome P450 enzymes in the liver.</p><p><strong>Methods: </strong>Quantifying CA and probe drugs <i>in vitro</i> samples and preclinical serum samples of male <i>SD</i> rats were performed using LC-MS/MS. The influence of CA on the hepatic CYPs and their gene expression was analyzed in rat liver by quantitative real-time polymerase chain reaction.</p><p><strong>Results: </strong>The plasma protein binding was found to be 84.81 ± 7.70 and 96.34 ± 3.12, blood-to-plasma ratio of 0.62 ± 0.16 and 0.80 ± 0.23 at 1 μM and 10 μM concentrations, respectively. Again, the absolute oral bioavailability of CA at 100 mg/kg was found to be 37.56 ± 7.3%. The <i>in-vivo</i> pharmacokinetic profile of probe drugs revealed CA to have significant inducing effects on CYP1A2, 2C11, 2D2, and 2E1 after 14 days, which correlates to both <i>in-vitro</i> rat microsomal data and gene expression results.</p><p><strong>Conclusion: </strong>Altogether, pharmacokinetic parameters reveal CA to have an affinity to distribute across different extravascular tissues and induce rat liver CYP enzymes.</p>","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":" ","pages":"587-598"},"PeriodicalIF":2.1000,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"1","resultStr":"{\"title\":\"Preclinical Pharmacokinetics and CYP Modulation Activity of Chebulinic Acid: A Potent Molecule Against Metabolic Disease.\",\"authors\":\"Arpon Biswas, Sarvesh Kumar Verma, Shiv Kumar, Tripti Mishra, Mukesh Kumar, Abhijit Deb Choudhury, Sristi Agrawal, Sachin Nashik Sanap, Amol Chhatrapati Bisen, Anjali Mishra, Tadigoppula Narender, Rabi Sankar Bhatta\",\"doi\":\"10.2174/1389200224666230817101950\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Chebulinic acid (CA) is an active constituent of <i>Terminalia chebula</i> fruits with therapeutic potential against multiple metabolic diseases, including dementia, benign prostate hyperplasia, and osteoporosis.</p><p><strong>Objective: </strong>The present work intends to explore the preclinical pharmacokinetics, including the absolute bioavailability of CA and its influence on the gene expression of cytochrome P450 enzymes in the liver.</p><p><strong>Methods: </strong>Quantifying CA and probe drugs <i>in vitro</i> samples and preclinical serum samples of male <i>SD</i> rats were performed using LC-MS/MS. The influence of CA on the hepatic CYPs and their gene expression was analyzed in rat liver by quantitative real-time polymerase chain reaction.</p><p><strong>Results: </strong>The plasma protein binding was found to be 84.81 ± 7.70 and 96.34 ± 3.12, blood-to-plasma ratio of 0.62 ± 0.16 and 0.80 ± 0.23 at 1 μM and 10 μM concentrations, respectively. Again, the absolute oral bioavailability of CA at 100 mg/kg was found to be 37.56 ± 7.3%. The <i>in-vivo</i> pharmacokinetic profile of probe drugs revealed CA to have significant inducing effects on CYP1A2, 2C11, 2D2, and 2E1 after 14 days, which correlates to both <i>in-vitro</i> rat microsomal data and gene expression results.</p><p><strong>Conclusion: </strong>Altogether, pharmacokinetic parameters reveal CA to have an affinity to distribute across different extravascular tissues and induce rat liver CYP enzymes.</p>\",\"PeriodicalId\":10770,\"journal\":{\"name\":\"Current drug metabolism\",\"volume\":\" \",\"pages\":\"587-598\"},\"PeriodicalIF\":2.1000,\"publicationDate\":\"2023-01-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"1\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Current drug metabolism\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.2174/1389200224666230817101950\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q4\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Current drug metabolism","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.2174/1389200224666230817101950","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q4","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
Preclinical Pharmacokinetics and CYP Modulation Activity of Chebulinic Acid: A Potent Molecule Against Metabolic Disease.
Background: Chebulinic acid (CA) is an active constituent of Terminalia chebula fruits with therapeutic potential against multiple metabolic diseases, including dementia, benign prostate hyperplasia, and osteoporosis.
Objective: The present work intends to explore the preclinical pharmacokinetics, including the absolute bioavailability of CA and its influence on the gene expression of cytochrome P450 enzymes in the liver.
Methods: Quantifying CA and probe drugs in vitro samples and preclinical serum samples of male SD rats were performed using LC-MS/MS. The influence of CA on the hepatic CYPs and their gene expression was analyzed in rat liver by quantitative real-time polymerase chain reaction.
Results: The plasma protein binding was found to be 84.81 ± 7.70 and 96.34 ± 3.12, blood-to-plasma ratio of 0.62 ± 0.16 and 0.80 ± 0.23 at 1 μM and 10 μM concentrations, respectively. Again, the absolute oral bioavailability of CA at 100 mg/kg was found to be 37.56 ± 7.3%. The in-vivo pharmacokinetic profile of probe drugs revealed CA to have significant inducing effects on CYP1A2, 2C11, 2D2, and 2E1 after 14 days, which correlates to both in-vitro rat microsomal data and gene expression results.
Conclusion: Altogether, pharmacokinetic parameters reveal CA to have an affinity to distribute across different extravascular tissues and induce rat liver CYP enzymes.
期刊介绍：
Current Drug Metabolism aims to cover all the latest and outstanding developments in drug metabolism, pharmacokinetics, and drug disposition. The journal serves as an international forum for the publication of full-length/mini review, research articles and guest edited issues in drug metabolism. Current Drug Metabolism is an essential journal for academic, clinical, government and pharmaceutical scientists who wish to be kept informed and up-to-date with the most important developments. The journal covers the following general topic areas: pharmaceutics, pharmacokinetics, toxicology, and most importantly drug metabolism.
More specifically, in vitro and in vivo drug metabolism of phase I and phase II enzymes or metabolic pathways; drug-drug interactions and enzyme kinetics; pharmacokinetics, pharmacokinetic-pharmacodynamic modeling, and toxicokinetics; interspecies differences in metabolism or pharmacokinetics, species scaling and extrapolations; drug transporters; target organ toxicity and interindividual variability in drug exposure-response; extrahepatic metabolism; bioactivation, reactive metabolites, and developments for the identification of drug metabolites. Preclinical and clinical reviews describing the drug metabolism and pharmacokinetics of marketed drugs or drug classes.
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