Danuta Szkutnik-Fiedler, Edyta Szałek, Filip Otto, Andrzej Czyrski, Marta Karaźniewicz-Łada, Anna Wolc, Edmund Grześkowiak, Konrad Lewandowski, Agnieszka Karbownik
{"title":"瑞戈非尼与阿托伐他汀在大鼠体内的药代动力学相互作用","authors":"Danuta Szkutnik-Fiedler, Edyta Szałek, Filip Otto, Andrzej Czyrski, Marta Karaźniewicz-Łada, Anna Wolc, Edmund Grześkowiak, Konrad Lewandowski, Agnieszka Karbownik","doi":"10.1007/s43440-024-00570-z","DOIUrl":null,"url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Background</h3><p>Regorafenib is used in the treatment of colorectal cancer and hepatocellular carcinoma. Due to the co-morbidity of hyperlipidemia in these conditions, statins, including atorvastatin, are used as potential adjuvant therapy agents. Both regorafenib and atorvastatin are metabolized by CYP3A4. In addition, atorvastatin is a P-gp and BCRP substrate, whereas regorafenib and its active metabolites M-2 and M-5 are inhibitors of these transporters. Hence, the concomitant use of both drugs may increase the risk of a clinically significant drug–drug interaction. Therefore, the present study aimed to assess the pharmacokinetic interactions of atorvastatin and regorafenib and their active metabolites.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>Male Wistar rats were assigned to three groups (eight animals in each) and were orally administered: regorafenib and atorvastatin (I<sub>REG+ATO</sub>), a carrier with regorafenib (II<sub>REG</sub>), and atorvastatin with a carrier (III<sub>ATO</sub>). Blood samples were collected for 72 h. UPLC-MS/MS was the method of measurement of regorafenib and atorvastatin concentrations. The pharmacokinetic parameters were calculated with a non-compartmental model.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>A single administration of atorvastatin increased the exposure to regorafenib and its active metabolites. In the I<sub>REG+ATO</sub> group, the <i>C</i><sub>max</sub>, AUC<sub>0–<i>t</i></sub>, and AUC<sub>0–∞</sub> of regorafenib increased 2.7, 3.2, and 3.2-fold, respectively. Atorvastatin also significantly increased the <i>C</i><sub>max</sub>, AUC<sub>0–<i>t</i></sub>, and AUC<sub>0–∞</sub> of both regorafenib metabolites. Regorafenib, in turn, decreased the AUC<sub>0–<i>t</i></sub> and AUC<sub>0–∞</sub> of 2-OH atorvastatin by 86.9% and 67.3%, and the same parameters of 4-OH atorvastatin by 45.0% and 46.8%, respectively.</p><h3 data-test=\"abstract-sub-heading\">Conclusions</h3><p>This animal model study showed a significant pharmacokinetic interaction between regorafenib and atorvastatin. While this interaction may be clinically significant, this needs to be confirmed in clinical trials involving cancer patients.</p><h3 data-test=\"abstract-sub-heading\">Graphical abstract</h3>\n","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":null,"pages":null},"PeriodicalIF":3.6000,"publicationDate":"2024-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Pharmacokinetic interaction between regorafenib and atorvastatin in rats\",\"authors\":\"Danuta Szkutnik-Fiedler, Edyta Szałek, Filip Otto, Andrzej Czyrski, Marta Karaźniewicz-Łada, Anna Wolc, Edmund Grześkowiak, Konrad Lewandowski, Agnieszka Karbownik\",\"doi\":\"10.1007/s43440-024-00570-z\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<h3 data-test=\\\"abstract-sub-heading\\\">Background</h3><p>Regorafenib is used in the treatment of colorectal cancer and hepatocellular carcinoma. Due to the co-morbidity of hyperlipidemia in these conditions, statins, including atorvastatin, are used as potential adjuvant therapy agents. Both regorafenib and atorvastatin are metabolized by CYP3A4. In addition, atorvastatin is a P-gp and BCRP substrate, whereas regorafenib and its active metabolites M-2 and M-5 are inhibitors of these transporters. Hence, the concomitant use of both drugs may increase the risk of a clinically significant drug–drug interaction. Therefore, the present study aimed to assess the pharmacokinetic interactions of atorvastatin and regorafenib and their active metabolites.</p><h3 data-test=\\\"abstract-sub-heading\\\">Methods</h3><p>Male Wistar rats were assigned to three groups (eight animals in each) and were orally administered: regorafenib and atorvastatin (I<sub>REG+ATO</sub>), a carrier with regorafenib (II<sub>REG</sub>), and atorvastatin with a carrier (III<sub>ATO</sub>). Blood samples were collected for 72 h. UPLC-MS/MS was the method of measurement of regorafenib and atorvastatin concentrations. The pharmacokinetic parameters were calculated with a non-compartmental model.</p><h3 data-test=\\\"abstract-sub-heading\\\">Results</h3><p>A single administration of atorvastatin increased the exposure to regorafenib and its active metabolites. In the I<sub>REG+ATO</sub> group, the <i>C</i><sub>max</sub>, AUC<sub>0–<i>t</i></sub>, and AUC<sub>0–∞</sub> of regorafenib increased 2.7, 3.2, and 3.2-fold, respectively. Atorvastatin also significantly increased the <i>C</i><sub>max</sub>, AUC<sub>0–<i>t</i></sub>, and AUC<sub>0–∞</sub> of both regorafenib metabolites. Regorafenib, in turn, decreased the AUC<sub>0–<i>t</i></sub> and AUC<sub>0–∞</sub> of 2-OH atorvastatin by 86.9% and 67.3%, and the same parameters of 4-OH atorvastatin by 45.0% and 46.8%, respectively.</p><h3 data-test=\\\"abstract-sub-heading\\\">Conclusions</h3><p>This animal model study showed a significant pharmacokinetic interaction between regorafenib and atorvastatin. While this interaction may be clinically significant, this needs to be confirmed in clinical trials involving cancer patients.</p><h3 data-test=\\\"abstract-sub-heading\\\">Graphical abstract</h3>\\n\",\"PeriodicalId\":19947,\"journal\":{\"name\":\"Pharmacological Reports\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":3.6000,\"publicationDate\":\"2024-04-18\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Pharmacological Reports\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1007/s43440-024-00570-z\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"PHARMACOLOGY & PHARMACY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Pharmacological Reports","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s43440-024-00570-z","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
Pharmacokinetic interaction between regorafenib and atorvastatin in rats
Background
Regorafenib is used in the treatment of colorectal cancer and hepatocellular carcinoma. Due to the co-morbidity of hyperlipidemia in these conditions, statins, including atorvastatin, are used as potential adjuvant therapy agents. Both regorafenib and atorvastatin are metabolized by CYP3A4. In addition, atorvastatin is a P-gp and BCRP substrate, whereas regorafenib and its active metabolites M-2 and M-5 are inhibitors of these transporters. Hence, the concomitant use of both drugs may increase the risk of a clinically significant drug–drug interaction. Therefore, the present study aimed to assess the pharmacokinetic interactions of atorvastatin and regorafenib and their active metabolites.
Methods
Male Wistar rats were assigned to three groups (eight animals in each) and were orally administered: regorafenib and atorvastatin (IREG+ATO), a carrier with regorafenib (IIREG), and atorvastatin with a carrier (IIIATO). Blood samples were collected for 72 h. UPLC-MS/MS was the method of measurement of regorafenib and atorvastatin concentrations. The pharmacokinetic parameters were calculated with a non-compartmental model.
Results
A single administration of atorvastatin increased the exposure to regorafenib and its active metabolites. In the IREG+ATO group, the Cmax, AUC0–t, and AUC0–∞ of regorafenib increased 2.7, 3.2, and 3.2-fold, respectively. Atorvastatin also significantly increased the Cmax, AUC0–t, and AUC0–∞ of both regorafenib metabolites. Regorafenib, in turn, decreased the AUC0–t and AUC0–∞ of 2-OH atorvastatin by 86.9% and 67.3%, and the same parameters of 4-OH atorvastatin by 45.0% and 46.8%, respectively.
Conclusions
This animal model study showed a significant pharmacokinetic interaction between regorafenib and atorvastatin. While this interaction may be clinically significant, this needs to be confirmed in clinical trials involving cancer patients.
期刊介绍：
Pharmacological Reports publishes articles concerning all aspects of pharmacology, dealing with the action of drugs at a cellular and molecular level, and papers on the relationship between molecular structure and biological activity as well as reports on compounds with well-defined chemical structures.
Pharmacological Reports is an open forum to disseminate recent developments in: pharmacology, behavioural brain research, evidence-based complementary biochemical pharmacology, medicinal chemistry and biochemistry, drug discovery, neuro-psychopharmacology and biological psychiatry, neuroscience and neuropharmacology, cellular and molecular neuroscience, molecular biology, cell biology, toxicology.
Studies of plant extracts are not suitable for Pharmacological Reports.
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号
