Abstract
SummaryLapatinib is a tyrosine kinase inhibitor used for the treatment of breast cancer. Paracetamol is an analgesic commonly applied to patients with mild or moderate pain and fever. Cancer patients are polymedicated, which involves high risk of drug interactions during therapy. The aim of the study was to assess the interaction between lapatinib and paracetamol in rats. The rats were divided into three groups of eight animals in each. One group received lapatinib + paracetamol (IL + PA), another group received lapatinib (IIL), whereas the last group received paracetamol (IIIPA). A single dose of lapatinib (100 mg/kg b.w.) and paracetamol (100 mg/kg b.w.) was administered orally. Plasma concentrations of lapatinib, paracetamol and its metabolites – glucuronide and sulphate, were measured with the validated HPLC-MS/MS method and HPLC-UV method, respectively. The pharmacokinetic parameters of both drugs were calculated using non-compartmental methods. The co-administration of lapatinib and paracetamol increased the area under the plasma concentration-time curve (AUC) and the maximum concentration (Cmax) of lapatinib by 239.6% (p = 0.0030) and 184% (p = 0.0011), respectively. Lapatinib decreased the paracetamol AUC0-∞ by 48.8% and Cmax by 55.7%. In the IL + PA group the Cmax of paracetamol glucuronide was reduced, whereas the Cmax of paracetamol sulphate was higher than in the IIIPA group. Paracetamol significantly affected the enhanced plasma exposure of lapatinib. Additionally, lapatinib reduced the concentrations of paracetamol. The co-administration of lapatinib decreased the paracetamol glucuronidation but increased the sulphation. The findings of this study may be of clinical relevance to patients requiring analgesic therapy.
Highlights
All the data were expressed as the mean value ± standard deviation (SD)
The most serious adverse reaction associated with paracetamol is hepatotoxic effect of one of its metabolites, i.e. N-acetyl-p-benzoquinone imine (NAPQI) [11]
Because paracetamol is widely available as an over-the-counter drug
Summary
Grunwaldzka 6, 60-780 Poznań, Poland 4 Department of Animal Science, Iowa State University, 239E Kildee Hall, Ames, IA 50011, USA 5 Hy-Line International, 2583 240th Street, Dallas Center, IA 50063, USA. Analgesic drugs are often administered to oncological patients [1]. Paracetamol effectively relieves pain due to selective inhibition of cyclooxygenase-2 (COX-2) and −3 (COX-3) in the central nervous system by interfering with descending serotoninergic pathways and, to some extent, by blocking the activity of pain mediators (bradykinine, substance P). Therapeutic doses are safe and tolerated well, but excessive intake of the drug may cause hepatotoxicity. Paracetamol is essentially metabolised in the liver. It is transformed by glucuronidation (40–60%) and sulphation (20–46%). Many authors proved that paracetamol is a substrate of Invest New Drugs (2018) 36:819–827
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