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Stereoselective disposition of flurbiprofen from a mutual prodrug with a histamine H 2 ‐antagonist to reduce gastrointestinal lesions in the rat
Author(s) -
Fukuhara Akira,
Imai Teruko,
Otagiri Masaki
Publication year - 1996
Publication title -
chirality
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.43
H-Index - 77
eISSN - 1520-636X
pISSN - 0899-0042
DOI - 10.1002/(sici)1520-636x(1996)8:7<494::aid-chir6>3.0.co;2-b
Subject(s) - chemistry , flurbiprofen , antagonist , prodrug , disposition , histamine , pharmacology , stereoselectivity , oligopeptide , stereochemistry , biochemistry , receptor , peptide , medicine , catalysis , psychology , social psychology
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 H 2 ‐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. © 1996 Wiley‐Liss, Inc.