Ibuprofen glucuronide

Figure 8-5 500-MHz stop-flow H NMR spectrum obtained for ibuprofen glucuronide ...

Ibuprofen is the most thoroughly researched 2-ary lpropionic acid. It is a relatively weak, non-selective inhibitor of COX. In epidemiological studies, ibuprofen compared to all other conventional NSAIDs, has the lowest relative risk of causing severe gastrointestinal side effects. Because of this, ibuprofen is the most frequently used OTC ( over the counter , sale available without prescription) analgesic. Ibuprofen is highly bound to plasma proteins and has a relatively short elimination half-life ( 2 h). It is mainly glucuronidated to inactive metabolites that are eliminated via the kidney. 

Johnson CH, Wilson ID, Harding JR, et al. NMR spectroscopic studies on the in vitro acyl glucuronide migration kinetics of Ibuprofen ((+/-)-(R,S)-2-(4-isobutylphenyl) propanoic acid), its metabolites, and analogues. Anal Chem. 2007 79(22) 8720-8727. 

Castillo, M. Smith, PC. Covalent Binding of Ibuprofen Acyl Glucuronide to Human Serum Albumin In Vitro, Pharm Res. 10(S2), 42 (1991). 

Castillo, M. Smith, P.C. Direct determination of ibupropfen and ibuprofen acyl glucuronide in plasma by high-performance liquid chromatography using solid-phase extraction. J.Chromatogr, 1993, 614, 109-116... 

Ibuprofen is metabolized in the liver, through the cytochrome P450 system. It undergoes glu-curonidation, and the glucuronidated metabolite is excreted through the urine. 

Carboxyl group clofibrate, ciprofibrate, etodolac, fenoprofen, ibuprofen, ketoprofen, naproxen (racemic > 5), valproic acid and formation of simvastatin and atorvastatin lactones via an intermediate acyl glucuronide Tertiary amines amitriptyline, chlorpheniramine, chlorpromazine, clozapine, cyproheptadine, diphenylamine, doxepin, imipramine, ketotifen, loxapine, promethazine, tripellenamine, trifluoperazine Aromatic heterocyclic amines croconazole, lamotrigine, nicotine (30X velocity than UGT1A3), 1-phenylimidazole, posaconazole, retigabine Primary and secondary amines ... 

The main metabolites of ibuprofen, the glucuronides of ibuprofen and of the side-chain hydroxylated derivative 2-[4-(2-hydroxy-2-methylpropyl)phenyl]propionic acid) and a side-chain oxidized compound 2-[4-(2-carboxy-2-methylpropyl)phenyl]-propionic acid) could be detected after SPE using a 250-MHz instrument (Figure 8-2) [10]. 

Chiral inversion is a unique metabolic pathway that is known to influence the plasma concentrations of some of the 2-APAs, such as ibuprofen and fenoprofen, but less so for other drugs such as ketoprofen and flurbiprofen (see Chap. 8). In addition to chiral inversion, these drugs are subject to drug-dependent stereoselectivity in microsomal oxidation and/or glucuronidation. 

UGT-catalyzed glucuronidation of the carboxylic acid group in drugs results in the formation of acyl glucuronides, which are intrinsically electrophilic in nature. Protein modification can occur via a simple transacylation reaction with a protein nucleophile(s) or by acyl migration within the f3-0-glucuronide unit to a reactive aldehyde intermediate. Detailed mechanistic discussion on this issue is provided with the NSAIDs ibufenac and ibuprofen in the following section. 

Amperozide, amphetamine, methamphetamine, bambuterol, antidepressants (paroxetine, fluvoxamine, mianserin, and citalopram), anabolic steroids (glucuronides) promethazine, methadone, haloperidol, ibuprofen, naproxen, ketoprofen, propofol, ropivacaine Pb(ll), Mn(ll)... 

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