AN EVALUATION OF AN ANTI-INFLAMMATORY-HISTAMINE H2 ANTAGONIST DRUG COMPLEX ON GASTRIC-EROSIONS IN THE RAT

The anti-inflammatory effect, gastrotoxicity and in vivo absorption pr operty of the drug complex esterified flurbiprofen (FP) with histamine H-2 antagonist, N-[3-{3-(1-piperidinylmethyl)phenoxy} propyl]-2-(2-hy droxyethylthio)acetamide (PPA), were compared with those of FP and FP methyl ester. The drug complex of FP with PPA (FP-PPA) was partly hydr olyzed in vitro in buffer (pH 1.2-7.4) in the presence or absence of p epsin and trypsin, slowly hydrolyzed in gastric mucosal homogenate and quickly hydrolyzed in 1 0% rat plasma (T 1/2 = 35 sec). The hydrolysi s rates of FP-PPA were the same as FP methyl ester in enzymatic and no nenzymatic medium. FP-PPA inhibited carrageenan-induced paw edema to t he 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 d ependent on the drug concentration in gastric mucosa, whereas FP-PPA i nduced minor gastric erosion even at high mucosal drug complex concent ration. These data suggested that FP-PPA, the drug complex of FP with histamine H-2 antagonist, causes less gastric damage than ester prodru gs like methyl ester or free drug, FP.