Stereoselective disposition of flurbiprofen from a mutual prodrug with a histamine H2-antagonist to reduce gastrointestinal lesions in the rat

Chirality. 1996;8(7):494-502. doi: 10.1002/(SICI)1520-636X(1996)8:7<494::AID-CHIR6>3.0.CO;2-B.

Abstract

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.

MeSH terms

  • Administration, Oral
  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / adverse effects
  • Anti-Inflammatory Agents, Non-Steroidal / chemistry*
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacokinetics*
  • Cytosol / metabolism
  • Digestive System / drug effects
  • Digestive System / metabolism
  • Esterases / metabolism
  • Flurbiprofen / adverse effects
  • Flurbiprofen / analogs & derivatives*
  • Flurbiprofen / chemistry*
  • Flurbiprofen / pharmacokinetics*
  • Gastric Mucosa / enzymology
  • Gastric Mucosa / metabolism
  • Histamine H2 Antagonists / adverse effects
  • Histamine H2 Antagonists / chemistry*
  • Histamine H2 Antagonists / pharmacokinetics*
  • Hydrolysis
  • In Vitro Techniques
  • Injections, Intravenous
  • Liver / metabolism
  • Male
  • Microsomes / metabolism
  • Piperidines / adverse effects
  • Piperidines / chemistry*
  • Piperidines / pharmacokinetics*
  • Prodrugs / adverse effects
  • Prodrugs / chemistry*
  • Prodrugs / pharmacokinetics*
  • Rats
  • Rats, Wistar
  • Stereoisomerism

Substances

  • Anti-Inflammatory Agents, Non-Steroidal
  • Histamine H2 Antagonists
  • Piperidines
  • Prodrugs
  • flurbiprofen N-(3-(3-(1-piperidinylmethyl)phenoxy)propyl)-2-(2-hydroxyethylthio)acetamide
  • Flurbiprofen
  • Esterases