STEREOSELECTIVE DISPOSITION OF FLURBIPROFEN FROM A MUTUAL PRODRUG WITH A HISTAMINE H-2-ANTAGONIST TO REDUCE GASTROINTESTINAL LESIONS IN THERAT

The in vitro and in vivo stereoselective hydrolysis characteristics of the mutual prodrug FP-PPA, which is a conjugate of flurbiprofen (FP) with the histamine H-2-antagonist PPA, to reduce gastrointestinal lesi ons induced by FP were investigated and compared with those of FP meth yl ester (rac-FP-Me) and FP ethyleneglycol ester (rac-FP-EG), The rac- FP derivatives were hydrolyzed preferentially to the (+)-S-isomer in p lasma and to the (-)-R-isomer in liver and small intestinal mucosa, In terestingly, in the gastric mucosa, the stereoselectivity of hydrolysi s of (-)-R-FP-PPA was opposite from that of rac-FP-Me and rac-FP-EG, w hich suggested that the stereoselective hydrolysis of FP-PPA was helpf ul in reducing gastric damage induced by (+)-S-FP. However, hydrolysis of all rac-FP derivatives was found to be catalyzed by carboxylestera ses in the gastric mucosa. The stereoselective disposition of FP enant iomers early after intravenous administration of rac-FP-PPA could be e xplained by the stereoselective formation of (-)-R-FP from rac-FP-PPA in the liver. (-)-R-FP-PPA was completely hydrolyzed to form (-)-R-FP in vivo, while 78% of (+)-S-FP-PPA was hydrolyzed to (+)-S-FP, with a corresponding decrease in the area under the curve. Twenty-five percen t of (+)-S-FP-PPA might be eliminated as the intact prodrug or its met abolites other than FP, The most important bioconversion of FP-PPA occ urred in plasma, and additional hydrolysis of the R-enantiomer in live r resulted in the stereoselectivity observed following both i.v. and p .o. administration. (C) 1996 Wiley-Liss, Inc.