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

Chirality
A FukuharaM Otagiri

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...Continue Reading

References

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Citations

Mar 16, 2011·European Journal of Drug Metabolism and Pharmacokinetics·Nuggehally R Srinivas
Oct 16, 1999·Journal of Controlled Release : Official Journal of the Controlled Release Society·M OtagiriA Fukuhara
Sep 23, 2010·Pharmaceutical Development and Technology·Bridg'ette IsraelAnthony C Capomacchia
Jul 28, 2010·The Journal of Pharmacology and Experimental Therapeutics·Keith MorrisonMartine Clozel
Feb 24, 2015·Evidence-based Complementary and Alternative Medicine : ECAM·Min ZhangXiao-Bo Li
Oct 5, 2010·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·N DasS K Shrivastava

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