Organ slices as an in vitro test system for drug metabolism in human liver, lung and kidney

Abstract

Metabolism of xenobiotics occurs mainly in the liver, but in addition, the lungs and kidneys may contribute considerably. The choice of the animal species during drug development as a predictive model for the human condition is often inadequate due to large interspecies differences. Therefore, a universal method for the preparation and incubation of human and animal liver, lung and kidney tissue is being developed for drug metabolism and toxicity testing using precision-cut organ slices. Human tissue was obtained from surgical waste material. Slices were made from rat and human liver, kidney and agar-filled (1.5%, w/v) lung tissue using a Krumdieck tissue slicer and incubated in six-well plates. The morphology and the ATP content show that viability is maintained during 3 hours of incubation. These organ slices show a variety of phase I (hydroxylation, oxidation and O- and N-deethylation) and phase II (glucuronidation and sulfation) metabolic routes using lidocaine, testosterone, 7-ethoxycoumarin and 7-hydroxycoumarin as substrates. The metabolic patterns and rates were found to be different for the various organs and species studied. The use of human tissue slices will enable us to collect more human-specific data on drug metabolism and toxicity. This may lead to a more adequate choice of animal species used during drug development and will result in a considerable reduction in the use of experimental animals.