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

Agnieszka Karbownik,Andrzej Czyrski,Natalia Kostewicz,Marta Karaźniewicz-Łada,Paulina Kaczmarska,Joanna Stanisławiak-Rudowicz,Danuta Szkutnik-Fiedler,Anna Wolc,Edyta Szałek,Małgorzata Bekier,Franciszek Główka,Edmund Grześkowiak

doi:10.3390/pharmaceutics12070600

Abstract

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−metformin and sorafenib−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–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−hydroxy atorvastatin (p = 0.0239) and 4−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.

Highlights

Hepatocellular carcinoma (HCC) is one of the most common primary malignant liver tumors whose morbidity is on the rise [1]
We found that the co-administration of sorafenib and atorvastatin could lead to a higher risk of adverse reactions to sorafenib, such as hand-foot syndrome, alopecia, gastrointestinal disorders, a hypertensive crisis, or cardiotoxicity [34]
Statins are commonly used by elderly patients that usually struggle with other conditions, including kidney and liver disorders

Summary

Introduction

Hepatocellular carcinoma (HCC) is one of the most common primary malignant liver tumors whose morbidity is on the rise [1]. Sorafenib is the first-line treatment for patients with HCC This tyrosine kinase inhibitor (TKI) is transported in the plasma predominantly in a protein-bound form (99.5%). It appears in the systemic circulation mostly unchanged (approximately 70−85%) or as a sorafenib N−oxide (SR_NO; approximately 9−16%). Sorafenib penetrates the liver possibly via organic cation transporter−1 (OCT1, gene SLC22A1) and organic anion transporting polypeptide 1B1/3 (OATP1B1/3; SLCO1B1/3) in humans, and in Rattus norvegicus, via Oatp1b2 (Slco1b2) as well. It is metabolized by CYP3A4 to pharmacologically active SR_NO and inactive sorafenib glucuronide (SR_G). Sorafenib is carried by efflux transporters—P−glycoprotein (P−pg; ABCB1, Abcb1a), breast cancer resistance protein (BCRP; ABCG2, Abcg2) and MRP3 (ABCC3, Abcc3)—which transport SR_G from the hepatocytes to the blood [5,6,7,8]

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