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We previously reported that the combinatorial use of sodium laurate (C12) with several amino acids such as taurine (Tau) and L-glutamine (L-Gln) enhanced the colonic absorption of phenol red with attenuating the local toxicity caused by C12. However, even these amino acids could not protect epithelial cells from being damaged if the mucosal damage got worse to the coagulation necrosis by an excessive dose of C12. Comparing C12 with sodium caprate (C10), used in drug products marketed, 100 μmol C10 was needed to exert the similar absorption-enhancement of rebamipide, a poorly absorbable antiulcer drug, to that by 10 μmol C12, and 100 μmol C10 was obviously more toxic to the mucosa than 10 μmol C12. The combinatorial use of C12 with Tau or L-Gln enhanced the colonic absorption of rebamipide four to nine times larger in AUC than the control. Histopathologic studies clearly showed that Tau and L-Gln exerted the cytoprotective action on epithelial cells suffering from slight damages such as shrinkage and exfoliation, more articulately at 6 h than at 1.5 h after dosing. In conclusion, the combinatorial use of C12 with Tau or L-Gln could lead to a novel formulation improving the bioavailability of poorly absorbable drugs without any serious local damages. © 2003 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 92: 911–921, 2003

To examine whether Long‐Evans Cinnamon (LEC) rats, a mutant rat model of Wilson's disease, have a susceptibility gene(s) to hepatocarcinogenesis in addition to the causative gene, Atp7b, we established a new congenic strain, WKAH.C‐Atp7brats, in which the Atp7bgene of the LEG rats is inserted into the normal Wistar‐King Aptekman Hokkaido (WKAH) background. Hepatocellular tumors developed spontaneously in both sexes of WKAH.C‐Atp7brats, their incidence being slightly lower than that in LEG rats. Incidences of spontaneous liver tumors in LEG, WKAH.C‐Atp7band WKAH rats correlated with hepatic copper and iron concentrations. Medium‐term liver bioassay showed that LEG rats were more susceptible to the induction of glutathione S‐transferase placental form‐positive preneoplastic foci than WKAH.C‐Atp7brats, and WKAH.C‐Atp7brats were more susceptible than WKAH rats. In an N‐diethylnitrosamine (DEN)‐induced long‐term carcinogenicity study, 1) LEC rats were similarly or rather less susceptible to hepatocellular tumors than WKAH.C‐Atp7band WKAH rats, indicating that the progression of the preneoplastic foci to liver cancer in LEG rats was worse than that in WKAH.C‐Atp7band WKAH rats, 2) the incidences of kidney tumors in LEG and WKAH.C‐Atp7brats were higher than that in WKAH rats and high copper concentrations in the kidneys were observed in LEG and WKAH.C‐Atp7brats, 3) LEC rats were resistant to lung carcinogenesis. These data indicate that the susceptibility of LEG rats to liver and kidney carcinogenesis could be explained by Atp7bgene mutation and that the susceptibility to lung carcinogenesis is controlled by gene(s) other than Atp7b.