Gemfibrozil and its oxidative metabolites: quantification of aglycones, acyl glucuronides, and covalent adducts in samples from preclinical and clinical kinetic studies

Hermening, Andreas; Gräfe, Ann-Katrin; Baktir, G.; Mutschler, E.; Spahn‐Langguth, Hildegard

doi:10.1016/s0378-4347(00)00041-4

Cited by 39 publications

(27 citation statements)

References 16 publications

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“…It is a lipid-regulating agent, which decreases serum triglycerides and very low density lipoproteins [12] and increases high density lipoproteins. It is still a drug of choice in the treatment of hyperlipidaemias involving raised triglyceride levels and has been effective in reducing the incidence of coronary heart disease [13].…”

Section: Introductionmentioning

confidence: 99%

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Flux enhancement of stagnant sandwich compared to supported liquid membrane systems in the removal of Gemfibrozil from waters

Molinari

Argurio

Poerio

2009

Journal of Membrane Science

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Section: Introductionmentioning

confidence: 99%

“…Renal extraction is the most important elimination pathway for the respective carboxylic acid as well as such glucorinides in men. Indeed, a total of 60-70% of the GEM dose is found in urine [12,14].…”

Section: Introductionmentioning

confidence: 99%

Flux enhancement of stagnant sandwich compared to supported liquid membrane systems in the removal of Gemfibrozil from waters

Molinari

Argurio

Poerio

2009

Journal of Membrane Science

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“…Although some targeted hepatic proteins were assigned, and glucuronyltransferase catalyzed diclofenac binding to rat liver homogenate (Hargus et al, 1994), the structures and metabolic derivations of modifications were not defined precisely. The method used often to characterize carboxylate-derived adducts of plasma proteins, namely alkalinolysis (Zia-Amirhosseini et al, 1994;Sallustio et al, 1997;Hermening et al, 2000), has not been applied to diclofenac patients. Correlations of plasma protein adduction with NSAID AG exposure in humans (Castillo et al, 1995), and especially the higher correlation with exposure to regioisomers (Hyneck et al, 1988), implicated covalent combination with AG and possibly intravascular reactions.…”

Section: Discussionmentioning

confidence: 99%

Mass Spectrometric Characterization of Circulating Covalent Protein Adducts Derived from a Drug Acyl Glucuronide Metabolite: Multiple Albumin Adductions in Diclofenac Patients

Hammond

Meng

Jenkins

et al. 2014

J Pharmacol Exp Ther

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Covalent protein modifications by electrophilic acyl glucuronide (AG) metabolites are hypothetical causes of hypersensitivity reactions associated with certain carboxylate drugs. The complex rearrangements and reactivities of drug AG have been defined in great detail, and protein adducts of carboxylate drugs, such as diclofenac, have been found in liver and plasma of experimental animals and humans. However, in the absence of definitive molecular characterization, and specifically, identification of signature glycation conjugates retaining the glucuronyl and carboxyl residues, it cannot be assumed any of these adducts is derived uniquely or even fractionally from AG metabolites. We have therefore undertaken targeted mass spectrometric analyses of human serum albumin (HSA) isolated from diclofenac patients to characterize drug-derived structures and, thereby, for the first time, have deconstructed conclusively the pathways of adduct formation from a drug AG and its isomeric rearrangement products in vivo. These analyses were informed by a thorough understanding of the reactions of HSA with diclofenac AG in vitro. HSA from six patients without drug-related hypersensitivities had either a single drug-derived adduct or one of five combinations of 2-8 adducts from among seven diclofenac N-acylations and three AG glycations on seven of the protein's 59 lysines. Only acylations were found in every patient. We present evidence that HSA modifications by diclofenac in vivo are complicated and variable, that at least a fraction of these modifications are derived from the drug's AG metabolite, and that albumin adduction is not inevitably a causation of hypersensitivity to carboxylate drugs or a coincidental association.

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“…Several reports on gemfibrozil determination have appeared in the literature. Gas chromatography [11] and high performance liquid chromatography (HPLC) with ultraviolet or fluorimetric detection [12][13][14][15][16][17][18][19] have been used for the determination of gemfibrozil and its metabolites in plasma and urine samples. A liquid chromatography-mass spectrometric method [20] has been reported for the determination of this drug in water and wastewater samples.…”

Section: Introductionmentioning

confidence: 99%

Development of a new analytical spectroscopic methodology based on the competitive aggregation in a dye–surfactant–drug system: Application to the determination of gemfibrozil

2008

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Abstract.A new analytical methodology based on the competitive aggregation in a dye-surfactant-drug system is developed for the determination of gemfibrozil. Eriochrome Blue Black R (EBBR) and Didodecyldimethylammonium bromide (DDABr) were the dye and surfactant used, respectively. In the proposed method, the anions of the dye bind to the cationic surfactant molecules to form dye-surfactant aggregates, which are monitored from changes in UV-Vis absorption features of the dye. In the ternary EBBR-DDABr-drug mixtures, the drug competes with the dye to interact with the surfactant, which results in a decrease in dye-surfactant aggregates formation. This, again, causes a change in absorption properties of the dye. The measurement parameter is the difference between the absorption of the dye in the presence and absence of the drug. In the appropriate experimental conditions the absorbance differences are directly proportional to the drug concentration. The influence of several experimental variables such as pH, concentrations of buffer, EBBR and DDABr on the measurement parameter were studied. Under the optimum conditions, the calibration graph was linear up to 6.0 µg ml −1 with the correlation coefficient of 0.998.The limit of detection and quantification were found to be 0.044 and 0.15 µg ml −1 , respectively. The method was validated and applied to the determination of gemfibrozil in pharmaceutical preparations.

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Gemfibrozil and its oxidative metabolites: quantification of aglycones, acyl glucuronides, and covalent adducts in samples from preclinical and clinical kinetic studies

Cited by 39 publications

References 16 publications

Flux enhancement of stagnant sandwich compared to supported liquid membrane systems in the removal of Gemfibrozil from waters

Flux enhancement of stagnant sandwich compared to supported liquid membrane systems in the removal of Gemfibrozil from waters

Mass Spectrometric Characterization of Circulating Covalent Protein Adducts Derived from a Drug Acyl Glucuronide Metabolite: Multiple Albumin Adductions in Diclofenac Patients

Development of a new analytical spectroscopic methodology based on the competitive aggregation in a dye–surfactant–drug system: Application to the determination of gemfibrozil

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