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.