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 (IIS), the second group received sorafenib + paracetamol (IS+PA), whereas the third group received only paracetamol (IIIPA). 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 (Cmax) of paracetamol by 33% (p = 0.0372). In the IS+ PA group the Cmax of paracetamol glucuronide was reduced by 48% (p =  < 0.0001), whereas the Cmax of paracetamol sulphate was higher by 153% (p = 0.0012) than in the IIIPA group. Paracetamol increased sorafenib and sorafenib N-oxide Cmax 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.

中文翻译：

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索拉非尼与对乙酰氨基酚在大鼠中的药物相互作用的体内评估。

用途索拉非尼是一种多靶点酪氨酸激酶抑制剂（TKI），用于治疗晚期肾细胞癌，肝细胞癌和放射性碘耐受性甲状腺癌。肿瘤性疾病是引起疼痛的原因，无论疾病的阶段如何，都可能发生。扑热息痛是一种非阿片类镇痛药，可单独使用或与阿片类药物联合使用以治疗癌症疼痛。大量研究指出，与扑热息痛并用时，TKIs的药代动力学参数会发生变化。该研究的目的是评估索拉非尼和扑热息痛之间的药物-药物相互作用（DDI）。方法将大鼠分为三组，每组八只动物。第一组接受索拉非尼（IIS），第二组接受索拉非尼+扑热息痛（IS + PA），而第三组仅接受扑热息痛（IIIPA）。口服单剂量索拉非尼（100 mg / kg bw）和扑热息痛（100 mg / kg bw）。索拉非尼及其代谢物-N-氧化物，扑热息痛及其葡糖醛酸和硫酸盐代谢物的血浆浓度采用经过验证的高效液相色谱（HPLC）方法进行紫外检测。结果索拉非尼和扑热息痛的共同给药使扑热息痛的最大浓度（Cmax）增加33％（p = 0.0372）。在IS + PA组中，扑热息痛葡糖醛酸苷的Cmax比IIIPA组降低了48％（p = 0.0001），而扑热息痛硫酸盐的Cmax则提高了153％（p = 0.0012）。扑热息痛使索拉非尼和索拉非尼N-氧化物Cmax分别增加60％（p = 0.0068）和83％（p = 0.0023）。