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.

ABSTRACT:The aim of this study was to evaluate drug metabolism in rat small intestinal and colon precision-cut slices during 24 h of incubation and the applicability of these slices for enzyme induction studies. Various parameters were evaluated: intracellular levels of ATP (general viability marker), alkaline phosphatase activity (specific epithelial marker), villin expression (specific epithelial marker), and metabolic rates of 7-ethoxycoumarin (CYP1A), testosterone (CYP3A and CYP2B), and 7-hydroxycoumarin (glucuronide and sulfate conjugation) conversions. ATP and villin remained constant up to, respectively, 5 and 8 h in small intestine and up to 24 h in colon. The metabolic rate remained constant in small intestinal slices up to 8 h and decreased afterward to 24 to 92%, depending on the substrate studied. The inducibility of metabolism in small intestinal and colon slices was tested with several inducers at various concentrations and incubation times. The following inducers were used: 3-methylcholanthrene, ␤-naphthoflavone, indirubin, and tertbutylhydroquinone (aryl hydrocarbon receptor ligands), dexamethasone (glucocorticoid receptor/pregnane X receptor ligand) and phenobarbital (constitutive androstane receptor ligand). After incubation with inducers, metabolic rates were evaluated with 7-ethoxycoumarin and testosterone (phase I) and 7-hydroxycoumarin (phase II) as substrate. All inducers elevated the metabolic rates consistent with the available published in vivo induction data. Induction of enzyme activity was already detectable after 5 h (small intestine) and after 8 h (colon) for 3-methylcholanthrene and ␤-naphthoflavone and was clearly detectable for all tested inducers after 24 h (up to 20-fold compared with noninduced controls). In conclusion, small intestinal and colon precision-cut slices are useful for metabolism and enzyme induction studies.

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A 62-yr-old white nonsmoking male, with no history of serious diseases, was referred to the emergency department due to increasing epigastric pain during the previous 2 days. Physical examination revealed clinical signs of peritonitis. Abdominal sonography demonstrated cholecystolithiasis and splenomegaly. Abdominal radiography showed pronounced air content of the intestinal loops. Based on these results, the diagnosis of acute biliary pancreatitis was suspected. The chest radiograph confirmed an intrathoracic mass located at the right side of the spine ( fig. 2) and abdominal computed tomography (CT) revealed massive peripancreatic exudation, cholecystolithiasis and splenomegaly. On examination of the chest CT, the intrathoracic mass was located close to the thoracic spine. It was 40620 mm in size, ovally shaped and even surfaced ( fig. 3).The patient was transferred to the intensive care unit for treatment of acute pancreatitis, and underwent an endoscopic retrograde cholangiography with papillotomy and extraction of numerous pigmentary gallstones. Laboratory signs of inflammation and cholestasis normalised during the following FIGURE 1. Peripheral blood smear taken on admission of the patient.

An investigation was conducted on 21 patients (16 men and five women; mean age 48.2 [34-67] years) with cirrhosis of the liver of various aetiologies to determine whether molsidomine, which selectively reduces pre-load with-out the development of tolerance, effects portal and cardiac haemodynamics in liver cirrhosis and portal hypertension. Intravenous injection of 2 mg molsidomine reduced the hepatic vein closing pressure after 30 min by 8% (P less than 0.05) and the hepatic vein closing pressure gradient by 13.4% (P less than 0.002). The cardiac output fell by 5.8% (P less than 0.02) and the mean systemic arterial pressure by 4.2% (P less than 0.003). The reduction in hepatic venous closing pressure gradient did not correlate with the fall in cardiac output and mean arterial pressure. In 15 of 21 patients the hepatic venous pressure fell, but in six patients (28.6%) the pressure was not reduced (non-responders). The latter failure of response was associated with marked ascites, significant functional liver decompensation and alcoholic liver cirrhosis. Preliminary long-term observations with molsidomine point to a reduction in portal pressure by as much as 40%. This suggests that the drug is suitable for preventing bleeding from oesophageal varices.

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