Species differences in the metabolism of ritobegron in vitro and assessment of potential interactions with transporters and cytochrome P450 enzymes.

Ritobegron, a selective ß3-adrenoceptor agonist, is the prodrug of the active compound, KUC-7322. We investigated species differences in its metabolism in vitro and the potential for drug-drug interactions with ritobegron. In rat, dog, monkey, and human liver microsomes, ritobegron was not metabolized by cytochrome P450 enzymes (CYPs). KUC-7322 was the only metabolite observed. Hydrolysis of ritobegron to KUC-7322 was likely catalyzed by carboxylesterases in human liver microsomes. The maximum velocity of the reaction (V(max))/Michaelis-Menten constant (K(m)) for hydrolysis of ritobegron to KUC-7322 was much higher in rat serum than those in other species. There were also species differences in the conjugation of KUC-7322. Sulfate conjugates of ritobegron were detected in all species, whereas glucuronide and glutathione conjugates of KUC-7322 were only observed in rat liver subcellular fractions. Ritobegron and KUC-7322 did not affect the CYP-mediated metabolism of probe substrates in human liver microsomes and organic anion transporter 1 (OAT1)-, OAT2-, OAT3-, organic cation transporter 2 (OCT-2)-, OCT3-, or organic cation/carnitine transporter 1 (OCTN1)-mediated uptake of probe substrates in S2 cells. Ritobegron, but not KUC-7322, inhibited P-glycoprotein-mediated digoxin transport in Caco-2 cells. Significant uptake of KUC-7322 was observed in OAT3-expressing S2 cells. Therefore, CYP-mediated drug-drug interactions are not likely when ritobegron is administered with CYP substrates or inhibitors. Ritobegron may increase the plasma concentrations of P-glycoprotein substrates, such as digoxin, and the plasma concentration of KUC-7322 may increase when it is administered in combination with OAT inhibitors such as probenecid.

Solvent cleaning of pole transformers containing PCB contaminated insulating oil.

In 1989, it was discovered that the recycled insulation oil in pole transformers for electric power supply was contaminated with trace amounts of polychlorinated biphenyls (PCBs; maximum 50 mg-PCB/kg-insulation oil). In order to remove the PCBs from transformer components using n-hexane as a solvent, we investigated the relationship between progressive stages of dismantling and cleaning results. The results are summarized as follows: (1) Based on the cleaning test results, we made an estimate of the residual PCB amount on iron and copper components. By dismantling the test pole transformers into the "iron core and coil portion" and cleaning the components, we achieved a residual PCB amount that was below the limit of detection (0.05 mg-PCB/kg-material). To achieve a residual PCB amount below the limit of detection for the transformer paper component, it was necessary to cut the paper into pieces smaller than 5 mm. We were unable to achieve a residual PCB amount below the limit of detection for the wood component. (2) Compared to Japan's stipulated limited concentration standard values for PCBs, the results of the cleaning test show that cleaning iron or copper components with PCBs only on their surface with the solvent n-hexane will satisfy the limited concentration standard values when care is taken to ensure the component surfaces have adequate contact with the cleaning solvent.

Malignant insulinoma which expressed a unique creatine kinase isoenzyme: clinical value of arterial embolization as a palliative therapy.

A 76-year-old man with hypoglycemic coma was diagnosed as malignant insulinoma with multiple hepatic metastases. Embolization was done for two-thirds of the hepatic mass and it rapidly lowered the serum immunoreactive insulin. He was discharged without medication and has been free from hypoglycemia. After the embolization, the serum creatine kinase (CK) level increased transiently although there was no evidence of myocardial infarction. On electrophoresis, the CK activity showed an abnormal peak, suggesting mitochondrial CK. CK release after embolization has been reported in only a few cases with endocrine tumors, which might indicate some relationship between active energy metabolism and mitochondrial CK.

Submucosal hematoma producing mechanical obstruction in the sigmoid colon, complicated by systemic amyloidosis.

A case of systemic amyloidosis involving the gastrointestinal tract is presented. The initial manifestation of this case was mechanical obstruction. On laparotomy, a submucosal hematoma of the sigmoid colon which completely obliterated the lumen, was found. With intense medical treatment, the obstructed lumen became patent, but segmental ischemic colitis ensued. The terminal course of this case was complicated by chronic renal failure, upper gastrointestinal bleeding and coagulopathy. Pathological examination of the stomal specimen revealed massive amyloid deposits in the wall of the large intestine as well as other vital organs.

Significance of abnormal gastrointestinal gas in systemic amyloidosis.

Nine cases of amyloidosis involving the gastrointestinal tract were reviewed for the presence of abnormal gastrointestinal gas by taking plain roentgenograms of the abdomen (PRA) as a diagnostic adjunct. Findings were compared to data obtained by conventional barium study or endoscopic examination. PRA revealed marked gaseous dilatation of the gastrointestinal tract simulating intestinal obstruction in three cases and a moderate or mild increase of gas in two cases each. Abnormality was thus found in seven of the nine cases by PRA. Conventional barium study by means of upper gastrointestinal series, small bowel series and barium enema showed abnormal findings in five of seven cases. Endoscopic examination of the stomach and distal colon disclosed mucosal abnormality in three of seven cases. The rate of abnormal findings detected by the three methods cannot easily be compared to each other because of the differences in symptoms and treatment of individual patients. Nevertheless, PRA seem to be valuable in demonstrating a high rate of abnormalities in amyloidosis.