Drug-metabolizing activity of human and rat liver, lung, kidney and intestine slices

Abstract

1. Organ-specific biotransformation was studied in human and rat liver, lung, kidney and small intestine slices and compared on a protein basis, using four model substances. 2. Deethylation of lidocaine was highest in liver slices from both man and rat, followed by the small intestine. 3. Metabolism of testosterone was highest in liver slices, but a different overall metabolic pattern was found between the different organs. 4. Lung, kidney and intestine slices prepared from human and rat organs showed mainly an unknown metabolite of 7-ethoxycoumarin identified as 4-ethoxy-2-hydroxyphenyl propionic acid (EPPA). 5. The maximal metabolism of 7-ethoxycoumarin in slices was equal with in vivo V(max) in the rat. 6. Phase II metabolism of 7-hydroxycoumarin in kidney and intestinal slices was about 60% of the activity in liver slices. 7. In conclusion, organs other than the liver show a surprisingly high drug-metabolizing activity. Thus, the use of precision-cut slices of a combination of drug metabolizing organs in an in vitro test system from both animal and human origin is required for a proper systematic prediction of drug metabolism in man.

An in vitro method of alcoholic liver injury using precision-cut liver slices from rats

“…This finding was ascertained by both morphological and biochemical analysis of triglycerides. In this regard, triglyceride levels progressively increased during incubation in the presence of ethanol, reaching an almost In summary, PCLS have recently been used by other investigators studying the toxicological effects of a number of drugs and toxins [10,13,32,34]. It was the purpose of this study to determine whether PCLS could be used as a model system to study the effects of ethanol on the liver.…”

“…Others have used liver slices in the past to attempt to investigate the effects of ethanol on the liver; however, as with isolated cells and cell lines, these slices rapidly lost all normal liver function [16,[28][29][30][31]. Recently, investigators have developed precision-cut liver slices (PCLS), incubated under high oxygen content, for investigating the effects of various toxins on the liver [10,14,32,33]. As described in this manuscript, we have tested the applicability of using PCLS as a model for studying the mechanism(s) of alcoholinduced liver injury.…”

“…It should be noted, that it was necessary to use the incubator and roller inserts as described by [34] in order to maintain PCLS function for longer than 24 h. Additionally, the V7 medium used for cutting these slices and the addition of new media daily was imperative in maintaining the viability of the PCLS. Importantly, in our hands the use of alternative technological approaches; submerged slices in six-well plates on a rocker platform [35], Transwell Permeable Supports (Corning Inc. Acton, MA) on a rocker platform [14], Transwell plates with nitrocellulose [36], or home-made incubators to increase oxygen content [32] could only be used for short term cultures.…”

Novel biotransformation and physiological properties of norursodeoxycholic acid in humans†‡

“…Precision-cut liver slices (8-mm diameter and 250-m thickness) were prepared with a Krumdieck tissue slicer as described. 15,16 Slices were incubated in 3.2 mL Williams Medium E with 25 mmol/L glucose and gassed with 95%O 2 /5%CO 2 . After a preincubation of 60 minutes, 10 mol/L UDCA containing tracer [22, H]-UDCA or 10 mol/L norUDCA containing tracer [23-14 C]-norUDCA was added and the slices were incubated for an additional 3 and 16 hours.…”

“…Human liver slices have proved useful for the study of human-specific drug metabolism, having drug metabolizing capacities that correspond to in vivo values. [15][16][17] The chemical structure of norUDCA and UDCA are shown in Fig. 1.…”