The anti-inflammatory effect, gastrotoxicity and in vivo absorption property of the drug complex esterified flurbiprofen (FP) with histamine H2 antagonist, N-[3-(3-(1-piperidinylmethyl)phenoxy)propyl]-2- (2-hydroxyethylthio)acetamide (PPA), were compared with those of FP and FP methyl ester. The drug complex of FP with PPA (FP-PPA) was partly hydrolyzed in vitro in buffer (pH 1.2-7.4) in the presence or absence of pepsin and trypsin, slowly hydrolyzed in gastric mucosal homogenate and quickly hydrolyzed in 10% rat plasma (T1/2 = 35 sec). The hydrolysis rates of FP-PPA were the same as FP methyl ester in enzymatic and nonenzymatic medium. FP-PPA inhibited carrageenan-induced paw edema to the same extent as did FP alone. The plasma concentrations of FP after oral administration of FP derivatives were similar to FP alone. FP-PPA significantly reduced gastrotoxicity in comparison with an equivalent dose of FP, whereas the coadministration of FP and PPA did not affect the gastrotoxicity of FP. The gastrotoxicity of FP methyl ester was dependent on the drug concentration in gastric mucosa, whereas FP-PPA induced minor gastric erosion even at high mucosal drug complex concentration. These data suggested that FP-PPA, the drug complex of FP with histamine H2 antagonist, causes less gastric damage than ester prodrugs like methyl ester or free drug, FP.