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

Agnieszka Karbownik1, Danuta Szkutnik-Fiedler1, Andrzej Czyrski2

  • 1Department of Clinical Pharmacy and Biopharmacy, Poznań University of Medical Sciences, 61-861 Poznań, Poland.

Pharmaceutics
|July 2, 2020
PubMed

Insights

Drug interactions between sorafenib and common medications for hyperlipidemia (atorvastatin) and type 2 diabetes (metformin) were studied in rats. Atorvastatin increased sorafenib levels, while metformin decreased them, highlighting potential clinical significance for hepatocellular carcinoma patients.

Area of Science:

  • Pharmacology and Drug Interactions
  • Hepatocellular Carcinoma (HCC) Treatment
  • Drug Metabolism and Pharmacokinetics

Background:

  • Sorafenib is a first-line treatment for HCC, a condition often accompanied by hyperlipidemia and type 2 diabetes mellitus (T2DM).
  • Organic cation transporters (OCT) and multidrug and toxin extrusion (MATE) proteins influence the efficacy of sorafenib, metformin, and atorvastatin.
  • Altered transporter activity can lead to clinically significant pharmacokinetic interactions between these drugs.

Purpose of the Study:

  • To investigate the pharmacokinetic interactions between sorafenib and metformin in a rat model.
  • To assess the pharmacokinetic interactions between sorafenib and atorvastatin in a rat model.
  • To evaluate the clinical relevance of these drug interactions in HCC patients with comorbidities.

Main Methods:

  • Rats were divided into five groups receiving sorafenib, atorvastatin, metformin, or combinations thereof.
  • Plasma concentrations of sorafenib, metformin, atorvastatin, and atorvastatin metabolites were measured.
  • Key pharmacokinetic parameters, including maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC), were analyzed.

Main Results:

  • Atorvastatin significantly increased sorafenib's Cmax (134.4%) and AUC (66.6%).
  • Sorafenib significantly increased atorvastatin's AUC (94.0%) and its metabolites' AUCs (55.3%–209.4%).
  • Metformin significantly decreased sorafenib's AUC by 40% (AUC ratio 0.6), while sorafenib did not significantly affect metformin exposure.

Conclusions:

  • Significant pharmacokinetic interactions occur between sorafenib and atorvastatin, and between sorafenib and metformin, in rats.
  • Atorvastatin enhances sorafenib exposure, whereas metformin reduces it.
  • These interactions may have clinical implications for managing HCC patients with coexisting hyperlipidemia or T2DM.
Keywords:
atorvastatindrug–drug interactionmetforminpharmacokineticssorafenibsorafenib N-oxide

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