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NMR Spectroscopic Studies on the in Vitro Acyl Glucuronide Migration Kinetics of Ibuprofen ((±)-(R,S)-2.(4-Isobutylphenyl) Propanoic Acid), Its Metabolites, and Analogues.
- Source :
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Analytical Chemistry . 11/15/2007, Vol. 79 Issue 22, p8720-8727. 8p. 2 Diagrams, 4 Charts, 1 Graph. - Publication Year :
- 2007
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Abstract
- Carboxylic acid-containing drugs are often metabolized to 1-β-O-acyi glucuronides (AGs). These can undergo an internal chemical rearrangement, and the resulting reactive positional isomers can bind to endogenous proteins, with clear potential for adverse effects. Additionally any 1-β-O-acyl-glucuronidated phase I metabolite of the drug can also show this propensity, and investigation of the adverse effect potential of a drug also needs to consider such metabolites. Here the transacylation of the common drug ibuprofen and two of its metabolites is investigated in vitro. 1-β-O-Acyl (S)-ibuprofen glucuronide was isolated from human urine and also synthesized by selective acylation. Urine was also used as a source of the (R)-ibuprofen, (S)-2-hydroxyibuprofen, and (S,S)-carboxyibuprofen AGs. The degradation rates (a combination of transacylation and hydrolysis) were measured using 1H NMR spectroscopy, and the measured decrease in the 1-β anomer over time was used to derive half-lives for the glucuronides. The biosynthetic and chemically synthesized (S)-ibuprofen AGs had half-lives of 3.68 and 3.76 h, respectively. (R)-Ibuprofen AG had a half-life of 1.79 h, a value approximately half that of the (S)-diastereoisomer, consistent with results from other 2-aryl propionic acid 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 were synthesized with the glucuronide carboxyl function esterified with either ethyl or allyl groups. The (S)-ibuprofen AG ethyl ester and (S)-ibuprofen AG allyl esters were determined to have half-lives of 7.24 and 9.35 h, respectively. In order to construct useful structure-reactivity relationships, it is necessary to evaluate transacylation and hydrolysis separately, and here it is shown that the (R)- and (S)-ibuprofen AGs have different transacylation properties. The implications of these findings are discussed in terms of structure-activity relationships. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 00032700
- Volume :
- 79
- Issue :
- 22
- Database :
- Academic Search Index
- Journal :
- Analytical Chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 27743358
- Full Text :
- https://doi.org/10.1021/ac071368i