The Analytical Pharmacology Core is equipped with the latest instruments and software necessary in support of preclinical investigations and Phase I or Phase II clinical trials of new drugs, imaging agents, and chemical compounds. The Analytical Pharmacology Group routinely works with complex bioanalytical test procedures and pharmacokinetic analyses to help investigators at the basic and clinical levels. The laboratory staff and scientists are skilled in method development and validation for analysis of drugs and metabolites in biological matrices, for example plasma, using advanced and sensitive techniques. While this core is available for all investigators at the Center, the investigators and the management of the core facilities will evaluate the feasibility before a planned study is initiated. We can conduct these analyses under Good Laboratory Practice (GLP) guidelines as needed.
Instrumentation
Available capabilities include chromatography (HPLC), spectroscopy (UV, FL), and capillary electrophoresis as well as LC/MS/MS. Our LC-MS/MS facilities include a 96-well plate autosampler (Shimadzu) and a triple quad LC-MS/MS and a high performance quadrupole time-of-flight (QqTOF) mass spectrometer from Applied Biosystems (MDS Sciex API 4000 and QqTOF Elite) with ES and APCI ionization. The API 4000™ LC/MS/MS System is an enhanced high-performance triple quadrupole mass spectrometer system with applications in protein and peptide analysis, small molecule analysis in drug metabolism and pharmacokinetic studies, and n-in-one cassette dosing analysis. System includes Turbo V™ Source, TurboIonSpray® probe, APCI probe, Analyst® software, and Data Acquisition Station. The QqTOF mass spectrometer with a mass range of m/z 5-40,000 also includes a data station and software to control the operation of the modules and for data acquisition and data processing on QSTAR LCMS systems. Software includes an automated metabolite identification program for rapid metabolite screening using MS and MS/MS experiments. The high data content of this system will allow for monitoring of wide range of drug-related metabolites and degradation products which have a wide range of molecular weights including proteins. Automated liquid-handling systems are also available to increase the throughput of the analyses. The Biomek 3000 Laboratory Automation Workstation in series with Biomek NX meets the demands of rapidly changing life science technology with simple, intelligent automation of liquid-handling tasks. Pipetting, diluting, and dispensing operations are performed quickly, easily, and automatically. The modular platform allows expansion of system capability to include plate heating and cooling, plate washing, high-density transfers, photometric measurement, and high-capacity operation. This fully automated system uses 96-well or 384-well plate formats. The entire system is controlled by Biomek software with an intuitive graphical interface.
Pharmacokinetics
The facility provides services for nonclinical and clinical pharmacokinetic (PK) analyses in support of pharmaceutical development or toxicity studies and this core lab is trained and experienced in the use of the modeling software WinNonlin (5.3). In-house test procedures and templates for pharmacokinetic analysis and reporting have been developed to obtain high-quality results with the data-analysis descriptions in the Study Protocol and/or other agreements made with the investigators. Clinical pharmacokinetic analysis and reporting is performed according to GLP principles.
MALDI Tissue Imaging
The molecular specificity and sensitivity of mass spectrometry (MS) has been employed in this facility as a new technology for direct mapping and imaging of small molecules (drugs) present in tissue. This technology has been developed using matrix-assisted laser desorption/ionization coupled to MS (MALDI MS). It joins techniques such as immunochemistry, fluorescence microscopy and autoradiology for the study of the spatial arrangement of molecules within biological tissues. However, this technique provides several more attractive features such as no labeling and no extraction step required, its ability to resolve a drug from its metabolites and wide varieties of applicable analytes due to the specificity and sensitivity of MS. Imaging of small molecules in tissue sections by Imaging Mass spectrometry (IMS) requires an entire tissue section to be analyzed through an ordered array of spots, or raster, in which spectra are acquired at intervals that define the image resolution.
Drug Delivery Technology
Delivery of hydrophobic drug compounds to the site of action is an ongoing problem in clinical research. Among the types of drug delivery vehicles used are cyclodextrans, drug-lipid complexes, liposomes, and solubilizing agents such as Cremophor®. However, many useful drugs are still limited by their solubility, pharmacokinetic profiles and bioavailability. This facility is specialized in drug delivery technology (DDT). Various PEG-lipid conjugates have been used as the DDT vehicles to improve oral bioavailability of poorly water-soluble drugs. The current DDT focuses specifically on the use of lipid-based formulations to enhance drug solubilization for intravenous administrations in animal models.
