Use of a human liver microsome bank in drug glucuronidation studies

Lacarelle, Bruno; Rajaonarison, J F; Gauthier, Thierry; Placidi, M; Catalin, J; Rahmani, Roger

doi:10.1016/0887-2333(91)90093-s

Cited by 6 publications

(2 citation statements)

References 11 publications

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“…Although most in vitro metabolic investigations are conducted with microsome treatment [10–13], esterase in plasma and red blood cells (RBC) is reported to be active in drug metabolism in some cases [9]. Therefore, it is conceivable that treatment of esterase may provide some valuable information pertaining to the metabolism of UTL-5g.…”

Section: Introductionmentioning

confidence: 99%

Using a simple HPLC approach to identify the enzymatic products of UTL-5g, a small molecule TNF-α inhibitor, from porcine esterase and from rabbit esterase

Swartz

Zhang

Valeriote

et al. 2013

Journal of Chromatography B

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UTL-5g is a novel small-molecule chemoprotector that lowers hepatotoxicity, nephrotoxicity, and myelotoxicity induced by cisplatin through TNF-α inhibition among other factors. As a prelude to investigating the metabolites of UTL-5g, we set out to identify the enzymatic products of UTL-5g under the treatment of both porcine liver esterase (PLE) and rabbit liver esterase (RLE). First, a number of mixtures made by UTL-5g and PLE were incubated at 25 °C. At predetermined time points, individual samples were quenched by acetonitrile, vortexed, and centrifuged. The supernatants were then analyzed by reversed-phase HPLC (using a C18 column). The retention times and UV/Vis spectra of individual peaks were compared to those of UTL-5g and its two postulated enzymatic products; thus the enzymatic products of UTL-5g were tentatively identified. Secondly, a different HPLC method (providing different retentions times) was used to cross-check and to confirm the identities of the two enzymatic products. Based on the observations, it was concluded that under the treatment of PLE, the major enzymatic products of UTL-5g were 5-methyliosxazole-3-carboxylic acid (ISOX) and 2,4-dichloroaniline (DCA). Treatment of UTL-5g by RLE also provided the same enzymatic products of UTL-5g from esterase. These results indicate that the peptide bond in UTL-5g was cleaved by PLE/RLE. Michaelis–Menten kinetics showed that the Km values of UTL-5g were 2.07 mM with PLE and 0.37 mM with RLE indicating that UTL-5g had a higher affinity with RLE. In summary, by a simple HPLC approach, we have concluded that the peptide bond in UTL-5g was cleaved by esterase from either porcine liver or rabbit liver in vitro and afforded DCA (at a mole ratio of 1:1) and ISOX. However, further studies are needed in order to determine whether UTL-5g is metabolized by microsomal enzymes to produce ISOX and DCA.

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Section: Introductionmentioning

confidence: 99%

Using a simple HPLC approach to identify the enzymatic products of UTL-5g, a small molecule TNF-α inhibitor, from porcine esterase and from rabbit esterase

Swartz

Zhang

Valeriote

et al. 2013

Journal of Chromatography B

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“…This liver was previously characterized for its CYP3A activity (Lacarelle et al, 1991). The use of the sample was authorized by the French National Ethics Committee when the liver could not be used for transplantation.…”

Section: In Vitro Interaction Between Cyclosporin a And Macrolide Antmentioning

confidence: 99%