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
Mar 1, 1976·The Journal of Pharmacy and Pharmacology·S S AdamsC G Mason
Jan 1, 1975·Journal of Medicinal Chemistry·M E Greig, R L Griffin
Nov 16, 1992·Chemico-biological Interactions·R B MelchertU A Boelsterli
Jan 1, 1992·Chirality·P J HayballF Bochner
Apr 1, 1992·Pharmaceutical Research·N Mørk, H Bundgaard
Jul 22, 1992·Biochemical Pharmacology·P J HayballF Bochner
Dec 1, 1991·Prostaglandins·B M PeskarK Brune
Mar 15, 1991·Experientia·K BruneB A Peskar
Jan 1, 1990·Chirality·M P Knadler, S D Hall
Jun 1, 1989·The Journal of Pharmacy and Pharmacology·F M WilliamsM D Rawlins
Oct 1, 1989·Journal of Pharmaceutical Sciences·S K Yang, X L Lu
Jun 1, 1989·Agents and Actions·G GeisslingerK Brune
Aug 1, 1988·Journal of Pharmaceutical Sciences·F JamaliA S Russell
Nov 1, 1980·The Journal of Pharmacy and Pharmacology·M W Whitehouse, K D Rainsford
Jul 1, 1984·Clinical Pharmacokinetics·A J Hutt, J Caldwell
Nov 1, 1981·Journal of Pharmacobio-dynamics·K YamaokaT Uno
Jan 1, 1995·Biological & Pharmaceutical Bulletin·A FukuharaM Otagiri
Aug 1, 1993·Pharmaceutical Research·V K TammaraM A Khan
Jan 7, 1993·Biochemical Pharmacology·N W McCrackenF M Williams
Citations
Jan 1, 1997·Chirality·Y YoshigaeM Otagiri
Mar 16, 2011·European Journal of Drug Metabolism and Pharmacokinetics·Nuggehally R Srinivas
May 7, 1998·Life Sciences·Y YoshigaeM Otagiri
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
Jun 22, 2012·Chirality·Ivonne LammersCees Gooijer
Oct 5, 2010·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·N DasS K Shrivastava