Zopolrestat as a Human Glyoxalase?I Inhibitor and Its Structural Basis.

Zopolrestat as a Human Glyoxalase?I Inhibitor and Its Structural Basis.

ChemMedChem. 2013 Jul 15;
Zhai J, Zhang H, Zhang L, Zhao Y, Chen S, Chen Y, Peng X, Li Q, Yuan M, Hu X

Old drugs new tricks: Zopolrestat, an aldose reductase inhibitor developed by Pfizer for the treatment of diabetic complications, is a potent competition inhibitor of human glyoxalase?I (GLOI) in?vitro. Crystal structures of GLOI in complex with zopolrestat and indomethacin, a nonsteroidal anti-inflammatory drug and moderate inhibitor of GLOI, provide a structural basis for the development of novel GLOI inhibitors with excellent pharmacokinetics profiles. HubMed – drug

An MEKC assay for the therapeutic drug monitoring of cefepime.

J Sep Sci. 2013 Jun 12;
Theurillat R, Sendi P, Thormann W

The development of a robust assay based on MEKC for cefepime in human serum and plasma with internal quality assurance is reported. Sample preparation comprises protein precipitation in the presence of SDS at pH 4.5. This is a gentle approach for which decomposition of cefepime during sample handling is negligible. After hydrodynamic sample injection of the supernatant, analysis occurs in a phosphate/borate buffer at pH 9.1 with 75 mM SDS using normal polarity and analyte detection at 257 nm. The MEKC run time interval and throughput are about 5 min and seven samples per hour, respectively. The calibration range for cefepime is 1-60 ?g/mL, with 1 ?g/mL being the LOQ. The performance of the assay with multilevel internal calibration was assessed with calibration and control samples. The assay is shown to be simple, inexpensive, reproducible, and robust. It was applied to determine cefepime levels in the sera of critically ill patients and to assess the instability of cefepime in patient and control samples. Our data revealed that serum containing cefepime can be stored at -20°C for a short time, whereas for long-term storage, samples have to be kept at -70°C. HubMed – drug

Aldehyde Oxidase 1 in Human Liver Cytosols:Quantitative Characterization of AOX1 Expression Level and Activity Relationship.

Drug Metab Dispos. 2013 Jul 15;
Fu C, Di L, Han X, Soderstrom CI, Snyder M, Troutman MD, Obach RS, Zhang H

Aldehyde oxidase 1 (AOX1) is a cytosolic enzyme highly-expressed in liver and plays a key role in metabolizing drugs containing aromatic azaheterocyclic substituents. Rapid metabolism catalyzed by AOX1 can cause a drug to exhibit high clearance, low exposure, and hence decreased efficacy or even increased toxicity (if AOX1 generated metabolites are toxic). There is a need to develop the correlation between AOX1 expression levels and AOX1-substrate clearance. A fast, sensitive and robust absolute quantification (AQUA) LC-MS/MS method was developed to quantify AOX1 in human liver cytosol for the first time. This LC-MS/MS method includes a straightforward ultrafiltration fractionation step and gives great selectivity and wide dynamic range (5.2 pM to 20.7 nM). The AOX1 levels in human liver cytosols of 20 donors were quantified using this method to investigate individual differences in AOX1 expression. No significant individual or gender differences in AOX1 levels were observed, although male exhibited a broader distribution than that of female (0.74 to 2.30 pmol/mg vs. 0.74 to 1.69 pmol/mg). The AOX1 protein levels measured by LC-MS/MS were consistent with those measured by an ELISA assay. Several donors have normal AOX1 protein level, but low enzyme activity, which might be due to cofactor deficiency, SNP or homodimer dissociation. Cytosols from donors with chronic alcohol consumption had low AOX1-catalyzed carbazeran oxidation activities (< 51 ?l/min/mg compared to a median value of 455 ?l/min/mg), but preserved similar AOX1 protein expression levels (~15% less than the median value). HubMed – drug

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