title: Pharmacokinetic drug-drug interaction between erlotinib and paracetamol: A potential risk for clinical practice.
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 Cmaxby 18.9%. The mean values of paracetamol glucuronide/paracetamol ratios for Cmaxwere 32.2% higher, whereas paracetamol sulphate/paracetamol ratios for Cmaxand AUC0-∞were 37.1% and 57.1% lower in the IIPRgroup, when compared to the IIIER+PRgroup.
  
  
  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.affiliation: Department of Clinical Pharmacy and Biopharmacy, Poznan University of Medical Sciences, Św. Marii Magdaleny 14, PL 61-861 Poznań, Poland.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Karbownik
authors.affiliation: Department of Clinical Pharmacy and Biopharmacy, Poznan University of Medical Sciences, Św. Marii Magdaleny 14, PL 61-861 Poznań, Poland.
authors.forename: Edyta
authors.initials: E
authors.lastname: Szałek
authors.affiliation: 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.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Sobańska
authors.affiliation: Polpharma Biologics, Trzy lipy 3, PL 80-172 Gdańsk, Poland.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Grabowski
authors.affiliation: 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.
authors.forename: Anna
authors.initials: A
authors.lastname: Wolc
authors.affiliation: Department of Clinical Pharmacy and Biopharmacy, Poznan University of Medical Sciences, Św. Marii Magdaleny 14, PL 61-861 Poznań, Poland.
authors.forename: Edmund
authors.initials: E
authors.lastname: Grześkowiak
mesh_terms: D000082:Acetaminophen / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D018712:Analgesics, Non-Narcotic / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D004347:Drug Interactions; D000069347:Erlotinib Hydrochloride / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D047428:Protein Kinase Inhibitors / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D011817:Rabbits; D012306:Risk
chemical_list: D018712:Analgesics, Non-Narcotic; D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D000082:Acetaminophen; D000069347:Erlotinib Hydrochloride
keywords: Erlotinib; OSI420; Paracetamol; Paracetamol glucuronide; Paracetamol sulphate