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Flurbiprofen (FP) was esterified with a histamine H2-antagonist, PPA (N-[3-(3-(1-piperidinylmethyl)phenoxy)-propyl]-2-(2- hydroxyethylthio)acetamide), to yield a chimera drug, FP-PPA, and its protective effect toward gastric lesions, other toxicities and the disposition kinetics were investigated, as compared to those of FP, in multiple oral administration to rats for 2 weeks. FP-PPA scarcely formed any disorder of the gastric mucosa following multiple oral administration. The body weight changes and hematological and serum biochemical parameters were found to be similar to those in the control group. Some drug metabolizing enzyme activities tested were the same as those of the control group. Further, the pharmacokinetic parameters were found to be the same after both single and multiple oral administration. On the other hand, in the FP treated group, the inhibition of body weight increase and changes in serum biochemical and hematological parameters were observed due to malabsorption. The absorption rate constant was increased significantly after multiple administration as compared to that of single administration. It is suggested that these changes in the absorption process of FP are due to variations in gastrointestinal permeability derived from gastrointestinal damage. The results obtained here indicate clearly that the chimera drug FP-PPA scarcely forms any disorder of the gastric mucosa, even after multiple oral administration, and is thus a potential candidate for oral use.

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Effect of Oral Multiple-Dose Administration of Anti-inflammatory Flurbiprofen Chimera Drug on Gastric Lesion, Other Toxicities and Disposition Kinetics.