In partnership with the Sugiyama Laboratory, Shimadzu Corporation has started research on quantitative analysis methods using LC/MS/MS (liquid chromatography mass spectrometry) to support drug discovery using microdosing.
Research into Using LC/MS/MS to Support Drug Discovery Using Microdosing
The RIKEN Innovation Center invited Professor Yuichi Sugiyama, Ph.D, of the Department of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences at the University of Tokyo to establish the Sugiyama Laboratory for the purpose of researching a system that provides comprehensive support for drug discovery by enabling in vitro and in vivo prediction of pharmacokinetics, efficacy, and toxicity, prediction of interactions between drugs, variations between individuals or different pathologies.
Shimadzu has joined a total of 25 companies in investing capital for establishing the Sugiyama Laboratory. In addition, Shimadzu has started developing an application system using its LCMS system and high-sensitivity separation technology for clinical trials of microdosing and studies of cassette dosing.
In recent years, there has been increasing interest in microdosing clinical trials throughout the world. Consequently, guidelines have been established for conducting these trials in Europe, the United States, and Japan. Microdosing clinical trials involve analyzing the pharmacokinetics of administering micro doses, such as 100µg or 1/100 of the dose estimated for pharmacological effect, of candidate drug compounds to human subjects at an early stage of drug discovery. Predicting the disposition at given clinical dosages based on these results will enable more rapid and efficient drug development by reducing the number of candidate drug compounds before starting Phase I drug trials.
Analytical methods used for microdosing trials include accelerator mass spectrometry (AMS) to measure the concentration of candidate compounds labeled with radioactive isotopes, highly sensitive LC/MS/MS to measure unlabeled candidate compounds, positron emission tomography (PET) to measure candidate compounds labeled with positron-emitting radionuclides.
LC/MS/MS is more useful than the other two methods because it can separate ultra-trace components with high sensitivity and enable pharmacokinetic, quantitative, and even structural analysis based on metabolites from unchanged candidate compounds. Furthermore, LC/MS/MS can be used in cassette dosing studies.
Cassette dosing allows comparing the pharmacokinetics of multiple candidate compounds under identical conditions and enables choosing the compound with the best pharmacokinetics from among those expected to be effective. Though it offers cost advantages reducing the number of subjects, administering multiple candidate compounds requires sophisticated prediction models because disposition must be predicted precisely before administering the candidates.
Shimadzu has been developing mass spectrometers that offer fast data measurement speeds and high reliability for detecting trace components in samples. By utilizing Shimadzu's LCMS system and high-sensitivity separation technology in the research at the Sugiyama Laboratory, the partners intend to establish quantitative methods using microdosing, including cassette dosing, for trace drug analysis and, thereby, make advancements in pharmacokinetic research.
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