William H Schaefer

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Statins are widely used to treat lipid disorders. These drugs are safe and well tolerated; however, in <1% of patients, myopathy and/or rhabdomyolysis can develop. To better understand the mechanism of statin-induced myopathy, we examined the ability of structurally distinct statins to induce apoptosis in an optimized rat myotube model. Compound A (a(More)
A rugged LC-MS/MS method was developed to quantify reduced and oxidized glutathione (GSH and GSSG, respectively) in rat hepatocytes. In addition, GSH conjugates can be detected, characterized and measured in the same analysis. Samples were treated with acetonitrile and iodoacetic acid to precipitate proteins and trap free GSH, respectively. These highly(More)
As a class, hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors can potentially cause skeletal myopathy. One statin, cerivastatin, has recently been withdrawn from the market due to an unacceptably high incidence of rhabdomyolysis. The mechanism underlying statin-induced myopathy is unknown. This paper sought to investigate the relationship(More)
One-dimensional proton NMR spectra of complex solutions provide rich molecular information, but limited chemical shift dispersion creates peak overlap that often leads to difficulty in peak identification and analyte quantification. Modern high-field NMR spectrometers provide high digital resolution with improved peak dispersion. We took advantage of these(More)
The application of bench-top ion-trap atmospheric pressure ionization mass spectrometry in the characterization of in vitro metabolites of glyburide is discussed. The metabolites formed in vitro by rat, dog, monkey and human liver microsomes were separated by reversed-phase high-performance liquid chromatography (HPLC) and characterized by mass spectrometry(More)
Mitochondrial toxicity has been a serious concern, not only in preclinical drug development but also in clinical trials. In mitochondria, there are several distinct metabolic processes including fatty acid β-oxidation, the tricarboxylic acid (TCA) cycle, and oxidative phosphorylation (OXPHOS), and each process contains discrete but often intimately linked(More)
In recent years, quantitative metabolomics has played increasingly important roles in pharmaceutical research and development. Metabolic profiling of biofluids and tissues can provide a panoramic view of abundance changes in endogenous metabolites to complement transcriptomics and proteomics in monitoring cellular responses to perturbations such as diseases(More)
A sensitive and selective chiral high performance liquid chromatographic method was developed for the direct determination of R- and S-warfarin enantiomers in human plasma. The method involved direct injection of human plasma onto a semipermeable surface (SPS) guard column, washing the proteins from the column with aqueous acetonitrile and back flushing the(More)
Glucuronidation is an important mechanism used by mammalian systems to clear and eliminate both endogenous and foreign chemicals. Many functional groups are susceptible to conjugation with glucuronic acid, including hydroxyls, phenols, carboxyls, activated carbons, thiols, amines, and selenium. Primary and secondary amines can also react with carbon dioxide(More)
An alternative on-line automated sample enrichment technique useful for the direct determination of various drugs and their metabolites in plasma is described for rapid development of highly sensitive and selective liquid chromatographic methods using mass spectrometric detection. The method involves direct injection of plasma onto an internal surface(More)