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

Abstract

<jats:p>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 &lt; 0.0001) and 66.6% (p &lt; 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.</jats:p>

Baicalin Enhanced Oral Bioavailability of Sorafenib in Rats by Inducing Intestine Absorption

“…The t 1/2 was approximately 6.83–14.12 h with a gradual decrease process. The pharmacokinetic properties of SOR in rats in our present findings seem to be consistent with other studies ( Paul et al, 2019 ; Karbownik et al, 2020 ). In addition, what is interesting in these data is that the pharmacokinetic profiles of SOR have been showed marked gender-specific differences.…”

Drug-Drug Interaction between Metformin and Sorafenib Alters Antitumor Effect in Hepatocellular Carcinoma Cells

“…Therefore, our limited sampling strategy (two sampling points at 2 and 6 h after administration) is a limiting factor to draw any conclusion about the pharmacokinetic interaction between metformin and sorafenib and this point deserves further characterization. According to the results of Karbownik et al (Karbownik et al, 2020), we should have expected a lower total exposure to sorafenib in our murine model cotreated with metformin. However, coadministration of sorafenib plus metformin was associated with a greater decrease in tumor volume compared to sequential therapy in our model, which suggests that the differential effects between the two regimens may be the result of pharmacodynamic rather than pharmacokinetic interactions.…”

“…Prior administration of metformin impacted neither the plasma concentrations of sorafenib 2 and 6 h after its administration, nor the intracellular bioavailability of sorafenib in HCC cells in vitro. Karbownik et al (Karbownik et al, 2020) recently showed that the concomitant administration of metformin (100 mg/kg) increases the clearance of sorafenib (100 mg/kg) in rats, which results in a lower sorafenib half-life (16.3 ± 3.7 vs 21.9 ± 7.8 h, p=0.0372). This result was obtained from complete sorafenib pharmacokinetics including sampling points up to 96 h. The difference was particularly significant during the terminal elimination phase (i.e.…”

“…In addition, drugs were administrated according to a single regimen, i.e concomitant administration. Recently, Karbownik and colleagues (Karbownik et al, 2020) reported that the co-administration of metformin (100 mg/kg) and sorafenib (100 mg/kg) to rats increased the clearance of sorafenib, resulting in a lower half-life of sorafenib. This study points a potential pharmacokinetic interaction between metformin and sorafenib.…”

Antiangiogenic Drugs in NASH: Evidence of a Possible New Therapeutic Approach

“…Another important aspect of the eventual use of sorafenib in NASH is the potential pharmacological interactions with antidiabetic or antihypertensive drugs that are commonly prescribed in NASH patients. Recently, Karbownik et al [ 115 ] investigated the pharmacokinetic interactions between sorafenib and metformin or atorvastatin in a rat model. The concomitant administration of sorafenib and metformin increases the clearance of sorafenib in rats, which results in a significantly lower sorafenib half-life (16.3 vs. 21.9 h).…”