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2600650222_ftp - Isomeric Inversion of...

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Isomeric Inversion of Ibuprofen (R)-Enantiomer in Humans D. G. KAISER", G. J. VANGIESSEN, R. J. REISCHER, and W. J. WECHTER Abstract 0 Enantiomeric compositions of the major urinary me- tabolites of ibuprofen [(RS)-2-(4-isobutylphenyl)propionic acid] were characterized after oral administration of the racemic mix- ture and oral administration of the individual enantiomers to nor- mal human volunteers. Resolution of the diastereomeric amides, formed by reaction of the urinary metabolites with (S)-(-)-a- methylbenzylamine, was achieved by GLC. Only the (I?)-(-)-enan- tiomer of the intact drug was inverted to its optical antipode, (S)- (+), in humans. However, both (S)-(+)- and (I?)-(-)-enantiomem of the intact drug were transformed independently in uiuo to the major metabolites, i.e., 2,4'-(2-hydroxy-2-methylpropyl)phenyl- propionic acid and 2,4'-(2-carboxypropyl)phenylpropionic acid. In uiuo metabolism of ibuprofen to its carboxy metabolite was not stereoselective. Keyphrases 0 Ibuprofen-isomeric inversion of enantiomers, de- termined by characterization of major urinary metabolites Iso- meric inversion-ibuprofen enantiomers, determined by charac- terization of major urinary metabolites 0 Enantiomers-ibupro- fen, isomeric inversion determined .by characterization of major urinary metabolites Extensive pharmacological, toxicological, and bio- chemical studies of ibuprofen1 [(RS)-2-(4-isobutyl- pheny1)propionic acid] (I) (1, 2), a potent orally ac- tive anti-inflammatory agent in animals (3-6) and humans (7-9), have been reported. Interest in the stereochemistry of the metabolism of I was stimulat- ed by the early report (1) that: (a) after oral adminis- tration of the racemic drug, the major metabolites ex- creted in human urine (IV and VII) were optically ac- tive; and (b) the in uiuo biological activities of the in- dividual enantiomers of the intact drug were equiva- lent. Subsequently, it was shown that, after oral admin- istration of the individual enantiomers of I, the major metabolites isolated from human urine were dextro- rotatory (5). Utilizing GLC methods for measuring the individual enantiomers (10-12), the facile epi- merization of the (R)-(-)-isomer of I to its optical antipode, 11, was observed prior to oxida- tive metabolism (13, 14). With the availability of suitable analytical meth- odology for separating the enantiomers of the major metabolites excreted in human urine (10,12), studies were designed to further characterize the epimeriza- tion of the @)-(-)-isomer and metabolism of I in hu- mans. EXPERIMENT A L Reagents and Materials-The I used in this study was synthe- sized*, and the and (I?)-(-)-isomers were resolved (uide infra). Compounds IV and VII, used for initial metabolite charac- Motrin, The Upjohn Co., and Brufen, The Boots Co., Ltd The Boots Co., Ltd., Nottingham, England. hydmxy metabolite IV: isomeric mixture v (S)-(+) VI: (R)-(-) carboxy metabolite W: isomeric mixture VIII (S)-(+)/(S)-(+) IX: (R)-(-)/(S)- (+) x (S)-(+)/(R)-(-) XI: (R)-(-)/(R)-(-) terization, were isolated and purified from human urine3. The par- tially resolved (R)-(-)-isomer of IV (i.e., VI) was synthesized' (15). Tridecanoic acid5, isophthalic acid6, (R)-(+)-a-methylben- zylamine7, (S)-(-)-a-methylbenzylamine7, and hydrocarbon-sta- bilized chloroforms were used as supplied. Stock solutions of 1,l'-
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2600650222_ftp - Isomeric Inversion of...

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