Many of the challenges posed by the quantitative analysis of drug candidates in biological fluids are met by atmospheric pressure ionization tandem mass spectrometry (MS/MS). However, the development of suitable methodology requires the determination and optimization of many compound-specific instrumental variables. At a minimum, the m/z values of a precursor ion and a product ion, along with the optimum collision energy, must be known in order to construct a suitable method. MS/MS method performance is particularly sensitive to collision energy, which must be near-optimum for each compound analysed. Conventionally, these instrumental parameters are determined by continuous infusion of a standard solution into the ion source and optimizing each individual parameter. This paper describes the application of a technique based on the triple quadrupole mass spectrometer which streamlines the development of quantitative MS/MS methods. Received 10 January 1997; Revised 11 February 1997; Accepted 11 February 1997 Rapid. Commun. Mass Spectrom. 11, 593-597 (1997 Advances in molecular biology and combinatorial chemistry are revolutionizing drug discovery, yielding compounds with enhanced potency in ever-increasing numbers. The ability to measure rapidly compound levels in biological matrices has a huge impact on a given discovery program. Rapid analyte quantitation radically compresses the dispositional evaluation of compounds and adds significant momentum to the drug discovery process. Unfortunately, the development of suitable methods and subsequent sample analysis often requires a significant amount of time relative to other activities within a program. Matrices such as blood plasma, serum, tissue homogenates and urine contain literally thousands of small molecules and often contain high levels of protein and ionic material. The bioanalytical task is exacerbated by species and intersubject differences, variable fluidity and low compound levels. Traditionally, development of methods is rate limiting because extraction conditions and chromatography must be developed and optimized. Bioanalytical quantitation requires the application of significant capital and human resources for successful and rapid completion.The complexity of common biological matrices requires that analytical methodology be brought to bear which is (1) specific for the analyte of interest, (2) sufficiently sensitive for the particular assay methodology and (3) amenable to automation. The one analytical technique which most closely meets these criteria is high-performance liquid chromatography (HPLC) coupled with atmospheric pressure ionization mass spectrometry (HPLC/API-MS). This is widely used in the pharmaceutical industry for bioanalytical quantitation and is generally considered to be the technique of choice for the analysis of drugs and metabolites.1-5 Single-quadrupole instruments are in wide use for this application, which typically involves detection of a mass-selected molecular ion or other ion containing the relevant intact molecular species...
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