title: Influence of cancer cachexia on drug liver metabolism and renal elimination in rats.
abstract: BACKGROUND
  Body wasting and cachexia change body composition and organ function, with effects on drug pharmacokinetics. The aim of this study was to investigate how cancer and cancer cachexia modify liver metabolism and renal drug elimination in rats.
  
  
  METHODS
  Nine male Wistar-Han rats received a single oral dose of midazolam and propranolol (markers of hepatic metabolism), and 10 rats received single intravenous dose of iohexol, a marker of glomerular filtration rate. After drug delivery, multiple dried blood samples were obtained within 2 h post-dose to evaluate drug pharmacokinetic profiles. After baseline sampling (D0), rats were injected with tumour cells. Drug application and blood sampling were repeated when rats developed tumours (Day 5-D5), and when rats were severely cachectic (Day 10-D10). Clearance (CL) and volume of distribution (Vd) of drugs were assessed with non-linear mixed effects modelling. Weight and body composition were measured on D0 and D10 and were related to pharmacokinetic parameters.
  
  
  RESULTS
  All three drugs showed non-significant trend towards increased CL and Vd on D5. On D10, midazolam and propranolol CL and midazolam Vd significantly decreased from baseline (-80.5%, -79.8%, and -72.0%, respectively, P < 0.05 for all). Iohexol CL decreased by 29.8% from baseline value on D10, which was related to body weight loss (Pearson's r = 0.837, P = 0.019).
  
  
  CONCLUSIONS
  Hepatic metabolism and renal drug elimination are significantly reduced in cachexia, which could increase risk of dose-related adverse events.
authors.affiliation: Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia.
authors.forename: Katja
authors.initials: K
authors.lastname: Cvan Trobec
authors.affiliation: Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia.
authors.forename: Mojca
authors.initials: M
authors.lastname: Kerec Kos
authors.affiliation: Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia.
authors.forename: Jurij
authors.initials: J
authors.lastname: Trontelj
authors.affiliation: Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia.
authors.forename: Iztok
authors.initials: I
authors.lastname: Grabnar
authors.affiliation: Applied Cachexia Research, Department of Cardiology, Charité Medical School, Campus Virchow-Klinikum, Berlin, Germany.
authors.forename: Anika
authors.initials: A
authors.lastname: Tschirner
authors.affiliation: Division of Innovative Clinical Trials, Department of Cardiology & Pulmonology, University Medicine Göttingen (UMG), Göttingen, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Palus
authors.affiliation: Applied Cachexia Research, Department of Cardiology, Charité Medical School, Campus Virchow-Klinikum, Berlin, Germany.|Division of Innovative Clinical Trials, Department of Cardiology & Pulmonology, University Medicine Göttingen (UMG), Göttingen, Germany.
authors.forename: Stefan D
authors.initials: SD
authors.lastname: Anker
authors.affiliation: Division of Innovative Clinical Trials, Department of Cardiology & Pulmonology, University Medicine Göttingen (UMG), Göttingen, Germany.
authors.forename: Jochen
authors.initials: J
authors.lastname: Springer
authors.affiliation: Department of Cardiology, General Hospital Celje, Celje, Slovenia.|Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.
authors.forename: Mitja
authors.initials: M
authors.lastname: Lainscak
keywords: Cachexia; Cancer; Drug metabolism; Liver metabolism; Pharmacokinetic; Renal function