Metabolism of pimobendan in long-term human hepatocyte culture: in vivo-in vitro comparison

Xenobiotica. 1995 Aug;25(8):811-23. doi: 10.3109/00498259509061896.


The aim of this study was to investigate further the potential of a new hepatocyte culture based on the hypothesis that liver cells in an appropriate in vitro environment (immobilizing gel technique) maintain high metabolic activity comparable with that in vivo. Pimobendan (UD-CG 115), a pyridazinone derivative, is a cardiotonic vasodilator that increases myocardial contractility through calcium sensitization and relaxation of vascular smooth muscle, probably due to phosphodiesterase inhibition. In man, pimobendan is O-demethylated to UD-CG 212. This latter is metabolized to O- and N-glucuronides. Pimobendan itself is also glucuronidated to a N-glucuronide. Human hepatocytes immobilized in collagen gel were incubated with pimobendan to investigate their metabolic activity in the long-term and to compare the results to the data from clinical trials. 14C-labelled pimobendan was incubated at two concentrations (10 and 100 microM) at day 3, 11 and 22 of culture, and samples were analysed after 4, 24 and 48-h incubation. Metabolic patterns were evaluated by hplc with radioactivity-, diode array-, and mass spectral-detection. In vitro, pimobendan was O-demethylated and subsequently O-glucuronidated. The rate of metabolism of pimobendan could be maintained in this culture system for > 3 weeks. However, the relative amount of a putative N-glucuronide under in vitro conditions was lower than in vivo.

Publication types

  • Clinical Trial
  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biotransformation
  • Cardiotonic Agents / metabolism*
  • Cardiotonic Agents / pharmacokinetics
  • Cells, Cultured
  • Cells, Immobilized
  • Chromatography, High Pressure Liquid
  • Collagen
  • Cytochrome P-450 Enzyme System / metabolism
  • Glucuronates / metabolism
  • Glucuronic Acid
  • Humans
  • Liver / cytology
  • Liver / metabolism*
  • Mass Spectrometry
  • Molecular Structure
  • Phosphodiesterase Inhibitors / metabolism
  • Phosphodiesterase Inhibitors / pharmacokinetics
  • Pyridazines / metabolism*
  • Pyridazines / pharmacokinetics
  • Vasodilator Agents / metabolism
  • Vasodilator Agents / pharmacokinetics


  • Cardiotonic Agents
  • Glucuronates
  • Phosphodiesterase Inhibitors
  • Pyridazines
  • Vasodilator Agents
  • pimobendan
  • Glucuronic Acid
  • Collagen
  • Cytochrome P-450 Enzyme System