A Pharmacokinetic Study of the Interaction Between Regorafenib and Paracetamol in Male Rats

<b>Background</b>: In clinical practice, the prevalent problem of polypharmacy could result in increased risks of drug-drug interactions. Regorafenib (REG) is commonly co-administered with paracetamol (PA) as a treatment protocol in cancer patients with pain therapy. <b>Purpose</b>: This study aimed to demonstrate the effect of paracetamol on the pharmacokinetic parameters of regorafenib and its metabolites following a single administration of both substances in rats. Additionally, the influence of REG and its metabolites on the pharmacokinetics of paracetamol was also determined. <b>Methods</b>: Twenty-four rats were divided randomly into three groups: REG group (II_REG, regorafenib 20 mg/kg, <i>n</i> = 8), PA group (III_PA, paracetamol 100 mg/kg, <i>n</i> = 8), and REG+PA co-administration group (I_REG+PA, REG 20 mg/kg and PA 100 mg/kg, <i>n</i> = 8). The concentrations of regorafenib, regorafenib-<i>N</i>-oxide (M-2), and <i>N</i>-desmethyl-regorafenib-<i>N</i>-oxide (M-5) were determined using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). The plasma concentrations of PA and its glucuronide (GPA) and sulfate (SPA) metabolites were measured using the validated high-performance liquid chromatography method with ultraviolet detection (HPLC-UV). The pharmacokinetic parameters were calculated using a non-compartmental model. The statistical evaluation was performed in the SAS program. <b>Results</b>: After the administration of PA, the C_max and AUC_0-∞ of REG increased by 890% and 1140%, respectively; for M-2, they increased by 220% and 170%, and for M-5, by 2130% and 1730% (C_max and AUC_0-∞, respectively). A difference in the ratio of M-2/REG for AUC_0-∞ and C_max between the groups was observed, but not for M-5/REG. The AUC_0-∞ for PA and GPA decreased by 20.7% and 51.1%, respectively, when PA was co-administered with REG. But the AUC_0-∞ for SPA increased by 91.35% in the I_REG+PA group. A difference in the ratio of GPA/PA for C_max and for SPA/PA for AUC_0-t and AUC_0-∞ between the groups was observed. <b>Conclusions</b>: Paracetamol increased the plasma exposure of regorafenib, M-2, and M-5, which may exacerbate the drug's side effects. In contrast, REG reduced paracetamol exposure and contributed to its faster elimination, which may reduce the analgesic and antipyretic effects of paracetamol. These findings suggest clinical relevance for oncology patients requiring analgesic treatment.