In vivo assessment of the drug interaction between sorafenib and paracetamol in rats

Abstract

Purpose Sorafenib is a multi-targeted tyrosine kinase inhibitor (TKI) used for the treatment of advanced renal cell carcinoma, hepatocellular carcinoma and radioactive iodine resistant thyroid carcinoma. Neoplastic diseases are the cause of pain, which may occur regardless of the stage of the disease. Paracetamol is a non-opioid analgesic used alone or in combination with opioids for the treatment of cancer pain. Numerous studies have pointed out changes in the pharmacokinetic parameters of TKIs when co-administered with paracetamol. The aim of the study was to assess drug-drug interactions (DDIs) between sorafenib and paracetamol. Methods Rats were divided into three groups, each consisting of eight animals. The first group received sorafenib (II S), the second group received sorafenib + paracetamol (I S+PA), whereas the third group received only paracetamol (III PA). A single dose of sorafenib (100 mg/kg b.w.) and paracetamol (100 mg/kg b.w.) was administered orally. The plasma concentrations of sorafenib and its metabolite-N-oxide as well as paracetamol and its glucuronide and sulphate metabolites were measured using validated high-performance liquid chromatography (HPLC) method with ultraviolet detection. Results The co-administration of sorafenib and paracetamol increased the maximum concentration (C max) of paracetamol by 33% (p = 0.0372). In the I S+ PA group the C max of paracetamol glucuronide was reduced by 48% (p = < 0.0001), whereas the C max of paracetamol sulphate was higher by 153% (p = 0.0012) than in the III PA group. Paracetamol increased sorafenib and sorafenib N-oxide C max by 60% (p = 0.0068) and 83% (p = 0.0023), respectively. Conclusions A greater knowledge of DDI between sorafenib and paracetamol may help adjust dose properly and avoid toxicity effects in individual patients.

The Combination of Gefitinib and Acetaminophen Exacerbates Hepatotoxicity via ROS-Mediated Apoptosis

“…When APAP was combined with gefitinib, we speculated that the gefitinib-induced liver injury was exacerbated by an increase in ROS produced by gefitinib and the promotion of hepatocyte apoptosis. In vivo, modeling studies have found the effect of APAP on the pharmacokinetic parameters of sorafenib, lapatinib, and erlotinib, which resulted in a significant increase in the area under the plasma concentration-time curve and the maximum concentration of the oncology drugs, which may increase the intensity of adverse effects due to en-hanced inhibition of p-glycoprotein by APAP (Karbownik et al, 2017(Karbownik et al, , 2018(Karbownik et al, , 2020. Patients taking imatinib concurrently with APAP for pain relief may experience severe hepatotoxicity and even death (Polson and Lee, 2005;Thia et al, 2008).…”

Investigation of N-Acetyltransferase 2-Mediated Drug Interactions of Amifampridine: In Vitro and In Vivo Evidence of Drug Interactions with Acetaminophen

“…However, several recent studies have provided evidence that acetaminophen may induce drug interactions by altering the pharmacokinetics of victim drugs. For example, systemic exposure to sorafenib, a tyrosine kinase inhibitor used for the treatment of advanced renal cell carcinoma, and its metabolite N-oxide sorafenib increased in the presence of acetaminophen in rats [ 26 ], which may be due to P-glycoprotein (P-gp) inhibition by acetaminophen [ 27 ]. In addition, acetaminophen increases the clearance of lamotrigine glucuronide conjugates, resulting in decreased systemic exposure to lamotrigine in humans [ 28 ].…”

The Influence of Paracetamol on the Penetration of Sorafenib and Sorafenib N-Oxide Through the Blood–Brain Barrier in Rats

“…Our previous pilot study showed that a single administration of sorafenib and paracetamol increased the plasma exposure to sorafenib and its active metabolite [18]. Therefore, the aim of this study was to determine the effect of paracetamol on the degree of sorafenib penetration through the blood-brain barrier (BBB).…”