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Sulfonylurea hypoglycemic agents have interindividual variability in the gastrointestinal absorption rate. However, the absorption mechanism at the intestinal epithelium has not yet been clarified. To elucidate contribution of the specific mechanism for transepithelial transport of sulfonylureas, the apical-to-basolateral and basolateral-to-apical transport studies of tolbutamide were carried out using Caco-2 cell monolayers cultured on the polycarbonate membrane. The transported amounts of the substrate were measured by HPLC to estimate the apparent permeability coefficients (P(app)). In the apical-to-basolateral flux, the transport activity of tolbutamide was facilitated when the pH of the apical medium was more acidic than the basolateral one. ATP-depletion decreased the P(app) of tolbutamide. The kinetic analysis of the permeation rate indicated that the saturable process largely contributed to the tolbutamide flux. The P(app) of tolbutamide was lowered by an ionophore and monocarboxylic acids, while dicarboxylic acids and the inhibitor for the anion exchanger had no effect. In addition, mutual inhibition with benzoic acid was observed in transepithelial transport of tolbutamide. On the other hand, the permeation rate of tolbutamide from the basolateral to apical side was concentration-independent and neither affected by metabolic inhibitors, probenecid nor inhibitors for P-glycoprotein. In conclusion, these results suggest that apical-to-basolateral transport of tolbutamide across the Caco-2 cell monolayers is mediated by the pH-dependent specific system, presumably shared with other organic anions such as benzoic acid.

A traditional Chinese herbal medicine, Kampo medicine, maoto, has been widely used in the treatment of febrile symptoms caused by viral infection. This herbal extract granule for oral use, however, is not well accepted by infants or young children due to its unpleasant taste and odor. Therefore, we prepared Kampo medicine, maoto, suppository and investigated the pharmaceutical and clinical e‹cacy of the suppository. Kampo medicine, maoto, granules were micropulverized and homogeneously dispersed into Hosco-H15 to prepare suppositories containing 0.25 to 1.0 g herbal extract by the conventional fusion method. Content of l-ephedrine, an index compound of Kampo medicine, maoto, in the extract granules and suppositories was determined by using a high performance liquid chromatographic method. Physicochemical experiments revealed that the suppository containing 0.5 g herbal extract had the most suitable melting point of 34°C. Contents of l-ephedrine in the suppository were constant, 93 96％ of those in the same amount of the extract granules in diŠerent three lots. Upper and lower portions of the suppository had the same content of l-ephedrine. The suppository maintained more than 95％ of l-ephedrine content through 6 months at 4°C, room temperature and 40°C, although maldistribution of the extract constituent was observed after storage at 40°C. The suppository was administered to 21 pediatric febrile patients at a dose of 1/3 to 2 full pieces depending on their body weight and physical status. Signiˆcant reduction ( p＜0.001) of body temperature from 39.5 to 37.5°C without serious adverse eŠects was observed in 17 patients who were monitored the clinical eŠects on the febrile symptoms. In conclusion, Kampo medicine, maoto, suppository was found to satisfy the physicochemical quality and quantity standards as well as to be clinically applicable to neonates, infants and children with viral febrile symptoms without any adverse eŠects.

A fluorescein-labeled dextran-glutathione conjugate (FD-GSH) was synthesized in order to examine its disposition in the body. GSH was covalently attached to the FITC-labeled dextran by the cyanogen bromide activation method. Mice were injected with FD-GSH through the tail vein, and the levels of FD-GSH in the blood and various organs were measured fluorometrically. A substantial level of FD-GSH was found in the liver and this reached a maximum at 6-8 h after the injection. The hepatic uptake clearance was estimated to be 0.541 +/- 0.014 ml/h/g tissue or 42.4 +/- 9.8 ml/h/kg body weight. FD--GSH accumulated in the liver for a long period, while the half-life of the conjugate in the blood circulation was 1.45h. The cumulative urinary and fecal excretions of FD-GSH were 14% and 4% of dose at 72h after the injection, respectively. A molecular design of the conjugate was discussed on the basis of the results.