{"title":"高尿酸血症对Sprague-Dawley大鼠药代动力学的影响","authors":"Xiaomeng Pan, Dandan Li, Yujuan Chen, JiaMian Lu, Yakun Yang, Yusong Guo, Dezhi Kong, Wei Guo","doi":"10.1007/s13318-025-00950-7","DOIUrl":null,"url":null,"abstract":"<p><strong>Background and objective: </strong>Hyperuricemia (HUA) is a metabolic disease closely associated with hypertension. It can induce liver damage, subsequently affecting drug metabolism. However, its specific impacts and underlying mechanisms remain unclear. Therefore, the pharmacokinetics and cytochrome P450 (CYP450) enzyme activities were investigated.</p><p><strong>Methods: </strong>Twelve healthy Sprague-Dawley rats were randomly assigned into two groups, a control group and an experimental group, with six animals per group. To establish the HUA model, rats in the experimental group received a subcutaneous injection of potassium oxonate (POx) (250 mg/kg), combined with oral administration of a fructose solution (5%, w/v). Serum biochemical parameters were subsequently evaluated, while histopathological examinations of liver and kidney tissues were performed. Plasma amlodipine (ALDP) levels were quantified by employing LC-MS/MS, and pharmacokinetic parameters were analyzed using DAS 3.0 software. Furthermore, activities of six major CYP450 enzyme isoforms were simultaneously determined through the cocktail method.</p><p><strong>Results: </strong>In the HUA-induced rats, significant elevations in serum uric acid (SUA), blood urea nitrogen (BUN), and creatinine (Cr) were observed, accompanied by distinct pathological lesions within hepatic and renal tissues. Pharmacokinetic analyses demonstrated marked increases in the peak plasma concentration (C<sub>max</sub>), terminal elimination half-life (t<sub>½</sub>), and time to reach peak concentration (T<sub>max</sub>) of ALDP, which were elevated by approximately 2.7-fold, 1.5-fold, and 2.1-fold, respectively. The apparent oral clearance (CL<sub>z</sub>/F) significantly decreased by half. Furthermore, the activities of six CYP450 enzymes notably decreased: CYP2E1 by 94%, CYP2C19 by 92%, CYP2C9 by 91%, CYP2D6 by 80%, CYP3A1 by 73%, and CYP1A2 by 7%.</p><p><strong>Conclusion: </strong>This study successfully established a stable rat model of HUA, and demonstrated that HUA specifically alters drug metabolism by causing liver damage and modulating CYP450 enzyme activities.</p>","PeriodicalId":11939,"journal":{"name":"European Journal of Drug Metabolism and Pharmacokinetics","volume":" ","pages":"327-339"},"PeriodicalIF":2.4000,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"The Impact of Hyperuricemia on Pharmacokinetics in Sprague-Dawley Rats.\",\"authors\":\"Xiaomeng Pan, Dandan Li, Yujuan Chen, JiaMian Lu, Yakun Yang, Yusong Guo, Dezhi Kong, Wei Guo\",\"doi\":\"10.1007/s13318-025-00950-7\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background and objective: </strong>Hyperuricemia (HUA) is a metabolic disease closely associated with hypertension. It can induce liver damage, subsequently affecting drug metabolism. However, its specific impacts and underlying mechanisms remain unclear. Therefore, the pharmacokinetics and cytochrome P450 (CYP450) enzyme activities were investigated.</p><p><strong>Methods: </strong>Twelve healthy Sprague-Dawley rats were randomly assigned into two groups, a control group and an experimental group, with six animals per group. To establish the HUA model, rats in the experimental group received a subcutaneous injection of potassium oxonate (POx) (250 mg/kg), combined with oral administration of a fructose solution (5%, w/v). Serum biochemical parameters were subsequently evaluated, while histopathological examinations of liver and kidney tissues were performed. Plasma amlodipine (ALDP) levels were quantified by employing LC-MS/MS, and pharmacokinetic parameters were analyzed using DAS 3.0 software. Furthermore, activities of six major CYP450 enzyme isoforms were simultaneously determined through the cocktail method.</p><p><strong>Results: </strong>In the HUA-induced rats, significant elevations in serum uric acid (SUA), blood urea nitrogen (BUN), and creatinine (Cr) were observed, accompanied by distinct pathological lesions within hepatic and renal tissues. Pharmacokinetic analyses demonstrated marked increases in the peak plasma concentration (C<sub>max</sub>), terminal elimination half-life (t<sub>½</sub>), and time to reach peak concentration (T<sub>max</sub>) of ALDP, which were elevated by approximately 2.7-fold, 1.5-fold, and 2.1-fold, respectively. The apparent oral clearance (CL<sub>z</sub>/F) significantly decreased by half. Furthermore, the activities of six CYP450 enzymes notably decreased: CYP2E1 by 94%, CYP2C19 by 92%, CYP2C9 by 91%, CYP2D6 by 80%, CYP3A1 by 73%, and CYP1A2 by 7%.</p><p><strong>Conclusion: </strong>This study successfully established a stable rat model of HUA, and demonstrated that HUA specifically alters drug metabolism by causing liver damage and modulating CYP450 enzyme activities.</p>\",\"PeriodicalId\":11939,\"journal\":{\"name\":\"European Journal of Drug Metabolism and Pharmacokinetics\",\"volume\":\" \",\"pages\":\"327-339\"},\"PeriodicalIF\":2.4000,\"publicationDate\":\"2025-07-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"European Journal of Drug Metabolism and Pharmacokinetics\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1007/s13318-025-00950-7\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2025/6/12 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q3\",\"JCRName\":\"PHARMACOLOGY & PHARMACY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"European Journal of Drug Metabolism and Pharmacokinetics","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s13318-025-00950-7","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/6/12 0:00:00","PubModel":"Epub","JCR":"Q3","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
The Impact of Hyperuricemia on Pharmacokinetics in Sprague-Dawley Rats.
Background and objective: Hyperuricemia (HUA) is a metabolic disease closely associated with hypertension. It can induce liver damage, subsequently affecting drug metabolism. However, its specific impacts and underlying mechanisms remain unclear. Therefore, the pharmacokinetics and cytochrome P450 (CYP450) enzyme activities were investigated.
Methods: Twelve healthy Sprague-Dawley rats were randomly assigned into two groups, a control group and an experimental group, with six animals per group. To establish the HUA model, rats in the experimental group received a subcutaneous injection of potassium oxonate (POx) (250 mg/kg), combined with oral administration of a fructose solution (5%, w/v). Serum biochemical parameters were subsequently evaluated, while histopathological examinations of liver and kidney tissues were performed. Plasma amlodipine (ALDP) levels were quantified by employing LC-MS/MS, and pharmacokinetic parameters were analyzed using DAS 3.0 software. Furthermore, activities of six major CYP450 enzyme isoforms were simultaneously determined through the cocktail method.
Results: In the HUA-induced rats, significant elevations in serum uric acid (SUA), blood urea nitrogen (BUN), and creatinine (Cr) were observed, accompanied by distinct pathological lesions within hepatic and renal tissues. Pharmacokinetic analyses demonstrated marked increases in the peak plasma concentration (Cmax), terminal elimination half-life (t½), and time to reach peak concentration (Tmax) of ALDP, which were elevated by approximately 2.7-fold, 1.5-fold, and 2.1-fold, respectively. The apparent oral clearance (CLz/F) significantly decreased by half. Furthermore, the activities of six CYP450 enzymes notably decreased: CYP2E1 by 94%, CYP2C19 by 92%, CYP2C9 by 91%, CYP2D6 by 80%, CYP3A1 by 73%, and CYP1A2 by 7%.
Conclusion: This study successfully established a stable rat model of HUA, and demonstrated that HUA specifically alters drug metabolism by causing liver damage and modulating CYP450 enzyme activities.
期刊介绍：
Hepatology International is a peer-reviewed journal featuring articles written by clinicians, clinical researchers and basic scientists is dedicated to research and patient care issues in hepatology. This journal focuses mainly on new and emerging diagnostic and treatment options, protocols and molecular and cellular basis of disease pathogenesis, new technologies, in liver and biliary sciences.
Hepatology International publishes original research articles related to clinical care and basic research; review articles; consensus guidelines for diagnosis and treatment; invited editorials, and controversies in contemporary issues. The journal does not publish case reports.
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