Agnieszka Karbownik1, Edyta Szałek1, Katarzyna Sobańska2, Tomasz Grabowski3, Anna Wolc4, Edmund Grześkowiak1. 1. Department of Clinical Pharmacy and Biopharmacy, Poznan University of Medical Sciences, Św. Marii Magdaleny 14, PL 61-861 Poznań, Poland. 2. Department of Clinical Pharmacy and Biopharmacy, Poznan University of Medical Sciences, Św. Marii Magdaleny 14, PL 61-861 Poznań, Poland. Electronic address: ksobanska@ump.edu.pl. 3. Polpharma Biologics, Trzy lipy 3, PL 80-172 Gdańsk, Poland. 4. Department of Animal Science, Iowa State University, 239E Kildee Hall, Ames, IA 50011, USA; Hy-Line International, 2583 240th Street, Dallas Center, IA 50063, USA.
Abstract
BACKGROUND: Erlotinib is a tyrosine kinase inhibitor available for the treatment of non-small cell lung cancer. Paracetamol is an analgesic agent, commonly used in cancer patients. Because these drugs are often co-administered, there is an increasing issue of interaction between them. OBJECTIVE: The aim of the study was to investigate the effect of paracetamol on the pharmacokinetic parameters of erlotinib, as well as the influence of erlotinib on the pharmacokinetics of paracetamol. METHODS: The rabbits were divided into three groups: the rabbits receiving erlotinib (IER), the group receiving paracetamol (IIPR), and the rabbits receiving erlotinib+paracetamol (IIIER+PR). A single dose of erlotinib was administered orally (25mg) and was administered intravenously (35mg/kg). Plasma concentrations of erlotinib, its metabolite (OSI420), paracetamol and its metabolites - glucuronide and sulphate were measured with the validated method. RESULTS: During paracetamol co-administration we observed increased erlotinib maximum concentration (Cmax) and area under the plasma concentration-time curve from time zero to infinity (AUC0-∞) by 87.7% and 31.1%, respectively. In turn, erlotinib lead to decreased paracetamol AUC0-∞ by 35.5% and Cmax by 18.9%. The mean values of paracetamol glucuronide/paracetamol ratios for Cmax were 32.2% higher, whereas paracetamol sulphate/paracetamol ratios for Cmax and AUC0-∞ were 37.1% and 57.1% lower in the IIPR group, when compared to the IIIER+PR group. CONCLUSIONS: Paracetamol had significant effect on the enhanced plasma exposure of erlotinib. Additionally, erlotinib contributed to the lower concentrations of paracetamol. Decreased glucuronidation and increased sulphation of paracetamol after co-administration of erlotinib were also observed.
BACKGROUND:Erlotinib is a tyrosine kinase inhibitor available for the treatment of non-small cell lung cancer. Paracetamol is an analgesic agent, commonly used in cancerpatients. Because these drugs are often co-administered, there is an increasing issue of interaction between them. OBJECTIVE: The aim of the study was to investigate the effect of paracetamol on the pharmacokinetic parameters of erlotinib, as well as the influence of erlotinib on the pharmacokinetics of paracetamol. METHODS: The rabbits were divided into three groups: the rabbits receiving erlotinib (IER), the group receiving paracetamol (IIPR), and the rabbits receiving erlotinib+paracetamol (IIIER+PR). A single dose of erlotinib was administered orally (25mg) and was administered intravenously (35mg/kg). Plasma concentrations of erlotinib, its metabolite (OSI420), paracetamol and its metabolites - glucuronide and sulphate were measured with the validated method. RESULTS: During paracetamol co-administration we observed increased erlotinib maximum concentration (Cmax) and area under the plasma concentration-time curve from time zero to infinity (AUC0-∞) by 87.7% and 31.1%, respectively. In turn, erlotinib lead to decreased paracetamol AUC0-∞ by 35.5% and Cmax by 18.9%. The mean values of paracetamol glucuronide/paracetamol ratios for Cmax were 32.2% higher, whereas paracetamol sulphate/paracetamol ratios for Cmax and AUC0-∞ were 37.1% and 57.1% lower in the IIPR group, when compared to the IIIER+PR group. CONCLUSIONS:Paracetamol had significant effect on the enhanced plasma exposure of erlotinib. Additionally, erlotinib contributed to the lower concentrations of paracetamol. Decreased glucuronidation and increased sulphation of paracetamol after co-administration of erlotinib were also observed.
Authors: Agnieszka Karbownik; Katarzyna Sobańska; Tomasz Grabowski; Joanna Stanisławiak-Rudowicz; Anna Wolc; Edmund Grześkowiak; Edyta Szałek Journal: Cancer Chemother Pharmacol Date: 2020-05-11 Impact factor: 3.333