Fukuhara A, Imai T, Otagiri M
Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Kumamoto University, Japan.
Chirality. 1996;8(7):494-502. doi: 10.1002/(SICI)1520-636X(1996)8:7<494::AID-CHIR6>3.0.CO;2-B.
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 H2-antagonist PPA, to reduce gastrointestinal lesions induced by FP were investigated and compared with those of FP methyl ester (rac-FP-Me) and FP ethyleneglycol ester (rac-FP-EG). The rac-FP derivatives were hydrolyzed preferentially to the (+)-S-isomer in plasma and to the (-)-R-isomer in liver and small intestinal mucosa. Interestingly, in the gastric mucosa, the stereoselectivity of hydrolysis of (-)-R-FP-PPA was opposite from that of rac-FP-Me and rac-FP-EG, which suggested that the stereoselective hydrolysis of FP-PPA was helpful in reducing gastric damage induced by (+)-S-FP. However, hydrolysis of all rac-FP derivatives was found to be catalyzed by carboxylesterases in the gastric mucosa. The stereoselective disposition of FP enantiomers early after intravenous administration of rac-FP-PPA could be explained 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 percent of (+)-S-FP-PPA might be eliminated as the intact prodrug or its metabolites other than FP. The most important bioconversion of FP-PPA occurred in plasma, and additional hydrolysis of the R-enantiomer in liver resulted in the stereoselectivity observed following both i.v. and p.o. administration.
对相互前药FP-PPA（氟比洛芬（FP）与组胺H2拮抗剂PPA的缀合物）的体外和体内立体选择性水解特性进行了研究，该前药用于减少FP诱导的胃肠道损伤，并与FP甲酯（外消旋-FP-Me）和FP乙二醇酯（外消旋-FP-EG）的水解特性进行了比较。外消旋-FP衍生物在血浆中优先水解为（+）-S-异构体，在肝脏和小肠黏膜中优先水解为（-）-R-异构体。有趣的是，在胃黏膜中，（-）-R-FP-PPA的水解立体选择性与外消旋-FP-Me和外消旋-FP-EG相反，这表明FP-PPA的立体选择性水解有助于减少由（+）-S-FP引起的胃损伤。然而，发现所有外消旋-FP衍生物的水解均由胃黏膜中的羧酸酯酶催化。静脉注射外消旋-FP-PPA后早期FP对映体的立体选择性处置可以通过肝脏中外消旋-FP-PPA立体选择性形成（-）-R-FP来解释。（-）-R-FP-PPA在体内完全水解形成（-）-R-FP，而78%的（+）-S-FP-PPA水解为（+）-S-FP，曲线下面积相应减小。25%的（+）-S-FP-PPA可能作为完整前药或除FP以外的其代谢产物被消除。FP-PPA最重要的生物转化发生在血浆中，肝脏中R-对映体的额外水解导致了静脉注射和口服给药后观察到的立体选择性。
