NMR Spectroscopic Studies on the in Vitro Acyl Glucuronide Migration Kinetics of Ibuprofen ((±)-(R,S)-2-(4-Isobutylphenyl) Propanoic Acid), Its Metabolites, and Analogues
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- 作者：Caroline H. Johnson ; Ian D. Wilson ; John R. Harding ; Andrew V. Stachulski ; Lisa Iddon ; Jeremy K. Nicholson ; John C. Lindon
- 刊名：Analytical Chemistry
- 出版年：2007
- 出版时间：November 15, 2007
- 年：2007
- 卷：79
- 期：22
- 页码：8720 - 8727
- 全文大小：133K
- 年卷期：v.79,no.22(November 15, 2007)
- ISSN：1520-6882
文摘
Carboxylic acid-containing drugs are often metabolized to1--O-acyl glucuronides (AGs). These can undergo aninternal chemical rearrangement, and the resulting reactive positional isomers can bind to endogenous proteins,with clear potential for adverse effects. Additionally any1--O-acyl-glucuronidated phase I metabolite of the drugcan also show this propensity, and investigation of theadverse effect potential of a drug also needs to considersuch metabolites. Here the transacylation of the commondrug ibuprofen and two of its metabolites is investigatedin vitro. 1--O-Acyl (S)-ibuprofen glucuronide was isolatedfrom human urine and also synthesized by selectiveacylation. Urine was also used as a source of the (R)-ibuprofen, (S)-2-hydroxyibuprofen, and (S,S)-carboxyibuprofen AGs. The degradation rates (a combination oftransacylation and hydrolysis) were measured using 1HNMR spectroscopy, and the measured decrease in the 1-anomer over time was used to derive half-lives for theglucuronides. The biosynthetic and chemically synthesized (S)-ibuprofen AGs had half-lives of 3.68 and 3.76h, respectively. (R)-Ibuprofen AG had a half-life of 1.79h, a value approximately half that of the (S)-diastereoisomer, consistent with results from other 2-aryl propionicacid drug AGs. The 2-hydroxyibuprofen and carboxyibuprofen AGs gave half-lives of 5.03 and 4.80 h, considerably longer than that of either of the parent drug glucuronides. In addition, two (S)-ibuprofen glucuronides weresynthesized with the glucuronide carboxyl function esterified with either ethyl or allyl groups. The (S)-ibuprofenAG ethyl ester and (S)-ibuprofen AG allyl esters weredetermined to have half-lives of 7.24 and 9.35 h, respectively. In order to construct useful structure-reactivityrelationships, it is necessary to evaluate transacylationand hydrolysis separately, and here it is shown that the(R)- and (S)-ibuprofen AGs have different transacylationproperties. The implications of these findings are discussed in terms of structure-activity relationships.