Drug candidates quantitative analysis

Jemal M. et al., 1999. A versatile system of high-flow high performance hquid chromatography with tadem mass spectrometry for rapid direct-injection analysis of plasma samples for quantitation of a /1-lactam drug candidate and its open-ring biotransformation product. Rapid Commun Mass Spectrom 13 1462. 

High-sensitivity techniques for the quantitation and characterization of circulating metabolites following administration of radiolabeled compounds are of critical importance to understand the safety and efficacy profiles of novel drug candidates. AMS is one of the most sensitive techniques for the detection of radiolabeled components. However, the high cost and slow throughput of AMS analysis preclude the routine use of the techniques for metabolism studies. 

Figure 3.2 A quantitative process pipeline model, illustrating the transfer of successful drug candidates from one stage to the next. Quantitative increases in drug candidate sample-generation volume are complemented by proportional increases in resources for sample analysis. (Courtesy of Milestone Development Services, Newtown, Pa., USA.)...

The in vitro approaches feature human liver microsome incubations that contain drug candidates at a range of concentrations that span the anticipated maximum steady state plasma levels. The microsomal incubations also contain a specific probe substrate where the concentration closely approximates that Km value for the reaction under investigation. Quantitative analysis of the specific marker metabolites and internal standards using MRM provides a simple assessment of the potential inhibitory effects drug candidates have on the metabolism of specific CYP probe substrates. 

The analysis of compounds of pharmaceutical relevance is one of the most promising application areas for CEC—MS, because it offers high sensitivity, high selectivity and structural information [38,98,99,105], Paterson et al. [105] utilized CEC—ESI-MS for the analysis of potential drug candidates down to the 1 ng/ml level in solid-phase extracts of plasma samples. Relative standard deviations of retention time and peak area of 0.4-1.7% and 2.6-10.7%, respectively, were achieved, which proves, that the method is also applicable to quantitative analysis. The analysis of a pair of... 

Jemal, M. Ouyang, Z. Xia, Y.-Q. Powell, M.L. A Versatile System of High-Flow High Performance Liquid Chromatography with Tandem Mass Spectrometry for Rapid Direct-Injection Analysis of Plasma Samples for Quantitation of a p -Lactam Drug Candidate and its Open Ring Biotransformation Product, Rapid Commun. Mass Spectrom. 13(14), 1462-1471 (1999). 

The determination of the concentration of a drug in plasma is an accepted surrogate marker for drug exposure. The use of LC-MS-based approaches for the quantitative analysis of a drug or its metabolite in a physiological sample such as plasma or serum is perhaps the hallmark of PK studies in drug discovery. The PK profiles derived from LC-MS data provide bioavailability and half-life information for drug candidates. These PK profiles are used to directly compare lead compounds and select specific compounds for further study. 

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