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.

Keywords: Drug–drug interaction; Paracetamol; Paracetamol glucuronide and paracetamol sulphate; Pharmacokinetics; Sorafenib; Sorafenib N-oxide.

Fig. 1

Plasma concentration–time profiles (Mean ± SD) in rats receiving paracetamol (III_PA) and sorafenib + paracetamol (I_S+PA) of paracetamol (a), paracetamol glucuronide (b) and paracetamol sulphate (c)

Fig. 2

Plasma concentration–time profiles (Mean ± SD) in rats receiving sorafenib (II_S) and sorafenib + paracetamol (I_S+PA) of sorafenib (a), sorafenib N-oxide (b)