NMR Spectroscopic Studies on the in Vitro Acyl Glucuronide Migration Kinetics of Ibuprofen ((+-)-(R,S)-2-(4-lsobutylphenyl) Propanoic Acid),Its Metabolites,and Analogues

摘要

Carboxylic acid-containing drugs are often metabolized to 1-beta-O-acyl 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-beta-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-beta-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)-carboxy-ibuprofen AGs.The degradation rates (a combination of transacylation and hydrolysis) were measured using 1H NMR spectroscopy,and the measured decrease in the 1-beta 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)-diastereoiso-mer,consistent with results from other 2-aryl propionic acid drug AGs.The 2-hydroxyibuprofen and carboxyibu-profen 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 es-terified witii 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 mat the (R)- and (S)-ibuprofen AGs have different transacylation properties.The implications of these findings are discussed in terms of structure-activity relationships.