RESUMO
A simple, reliable, and accurate method was developed for quantitative assessment of metabolite coverage in preclinical safety species by mixing equal volumes of human plasma with blank plasma of animal species and vice versa followed by an analysis using high-resolution full-scan accurate mass spectrometry. This approach provided comparable results (within (±15%) to those obtained from regulated bioanalysis and did not require synthetic standards or radiolabeled compounds. In addition, both qualitative and quantitative data were obtained from a single LC-MS analysis on all metabolites and, therefore, the coverage of any metabolite of interest can be obtained.
Assuntos
Cromatografia Líquida de Alta Pressão , Preparações Farmacêuticas/metabolismo , Espectrometria de Massas em Tandem , Animais , Área Sob a Curva , Cromatografia Líquida de Alta Pressão/normas , Humanos , Marcação por Isótopo , Nitrilas/sangue , Nitrilas/metabolismo , Nitrilas/normas , Preparações Farmacêuticas/sangue , Preparações Farmacêuticas/normas , Piperazinas/sangue , Piperazinas/metabolismo , Piperazinas/normas , Coelhos , Padrões de Referência , Espectrometria de Massas em Tandem/normas , Testes de Toxicidade , Ureia/análogos & derivados , Ureia/sangue , Ureia/metabolismo , Ureia/normasRESUMO
The National Cancer Institute (NCI) recently acquired a large supply of formulated products of amygdalin manufactured by Cyto Pharma of Mexico, for possible use in a clinical trial in the US. Tablets for oral administration and ampules of the injectable produce were obtained. Both forms were extensively analyzed and evaluated by several analytic and pharmaceutical laboratories under contract with the NCI. Analytic test procedures were developed to determine the chemical integrity and quantitative composition of the formulated products. Routine physical and biologic tests were also performed to evaluate the manufacturing quality of both dosage forms. The results indicate that both the oral and injectable forms of amygdalin were substandard by US criteria for manufactured pharmaceutical products. All samples were determined to be chemically subpotent, mislabeled, and of poor manufacturing quality. More than 20 samples of the ampules were found by visual inspection to contain microbial contamination. Other samples were found to be pyrogenic. Based on the results of the testing performed, both tablet and ampule forms of amygdalin manufactured by Cyto Pharma of Mexico are considered unfit for use in man.