Stereoselective disposition of flurbiprofen from a mutual prodrug with a histamine H2-antagonist to reduce gastrointestinal lesions in the rat.
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.
Fukuhara
A
A
Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Kumamoto University, Japan.
Imai
T
T
Otagiri
M
M
D000284:Administration, Oral; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects / Q000737:chemistry* / Q000493:pharmacokinetics*; D003600:Cytosol / Q000378:metabolism; D004064:Digestive System / Q000187:drug effects / Q000378:metabolism; D004950:Esterases / Q000378:metabolism; D005480:Flurbiprofen / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000493:pharmacokinetics*; D005753:Gastric Mucosa / Q000201:enzymology / Q000378:metabolism; D006635:Histamine H2 Antagonists / Q000009:adverse effects / Q000737:chemistry* / Q000493:pharmacokinetics*; D006868:Hydrolysis; D066298:In Vitro Techniques; D007275:Injections, Intravenous; D008099:Liver / Q000378:metabolism; D008297:Male; D008861:Microsomes / Q000378:metabolism; D010880:Piperidines / Q000009:adverse effects / Q000737:chemistry* / Q000493:pharmacokinetics*; D011355:Prodrugs / Q000009:adverse effects / Q000737:chemistry* / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar; D013237:Stereoisomerism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D006635:Histamine H2 Antagonists; D010880:Piperidines; D011355:Prodrugs; C080760:flurbiprofen N-(3-(3-(1-piperidinylmethyl)phenoxy)propyl)-2-(2-hydroxyethylthio)acetamide; D005480:Flurbiprofen; D004950:Esterases