Pharmacokinetic Interaction between Sorafenib and Atorvastatin, and Sorafenib and Metformin in Rats

Autor:	Edyta Szałek, Marta Karaźniewicz-Łada, Danuta Szkutnik-Fiedler, Agnieszka Karbownik, Franciszek K. Główka, Edmund Grześkowiak, Andrzej Czyrski, Małgorzata Bekier, Joanna Stanisławiak-Rudowicz, Paulina Kaczmarska, Anna Wolc, Natalia Kostewicz
Rok vydání:	2020
Předmět:	Sorafenib endocrine system diseases medicine.drug_class Atorvastatin Cmax lcsh:RS1-441 Pharmaceutical Science Pharmacology 030226 pharmacology & pharmacy Article Tyrosine-kinase inhibitor lcsh:Pharmacy and materia medica sorafenib N-oxide 03 medical and health sciences 0302 clinical medicine Pharmacokinetics Hyperlipidemia Medicine heterocyclic compounds drug–drug interaction neoplasms business.industry nutritional and metabolic diseases atorvastatin medicine.disease digestive system diseases Metformin 030220 oncology & carcinogenesis Hepatocellular carcinoma sorafenib metformin business pharmacokinetics medicine.drug
Zdroj:	Pharmaceutics Volume 12 Issue 7 Pharmaceutics, Vol 12, Iss 600, p 600 (2020)
ISSN:	1999-4923
DOI:	10.3390/pharmaceutics12070600
Popis:	The tyrosine kinase inhibitor sorafenib is the first-line treatment for patients with hepatocellular carcinoma (HCC), in which hyperlipidemia and type 2 diabetes mellitus (T2DM) may often coexist. Protein transporters like organic cation (OCT) and multidrug and toxin extrusion (MATE) are involved in the response to sorafenib, as well as in that to the anti-diabetic drug metformin or atorvastatin, used in hyperlipidemia. Changes in the activity of these transporters may lead to pharmacokinetic interactions, which are of clinical significance. The study aimed to assess the sorafenib&minus metformin and sorafenib&minus atorvastatin interactions in rats. The rats were divided into five groups (eight animals in each) that received sorafenib and atorvastatin (ISOR+AT), sorafenib and metformin (IISOR+MET), sorafenib (IIISOR), atorvastatin (IVAT), and metformin (VMET). Atorvastatin significantly increased the maximum plasma concentration (Cmax) and the area under the plasma concentration&ndash time curve (AUC) of sorafenib by 134.4% (p < 0.0001) and 66.6% (p < 0.0001), respectively. Sorafenib, in turn, caused a significant increase in the AUC of atorvastatin by 94.0% (p = 0.0038) and its metabolites 2&minus hydroxy atorvastatin (p = 0.0239) and 4&minus hydroxy atorvastatin (p = 0.0002) by 55.3% and 209.4%, respectively. Metformin significantly decreased the AUC of sorafenib (p = 0.0065). The AUC ratio (IISOR+MET group/IIISOR group) for sorafenib was equal to 0.6. Sorafenib did not statistically significantly influence the exposure to metformin. The pharmacokinetic interactions observed in this study may be of clinical relevance in HCC patients with coexistent hyperlipidemia or T2DM.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::6383cb2c4fdd7f01d2d7f038c842ae51 https://doi.org/10.3390/pharmaceutics12070600 Zobrazit plný text záznamu Plný text ve formátu PDF Plný text ve formátu HTML
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