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Development of a Quantitative SPE LC-MS/MS Assay for Bradykinin in Human Plasma

IN T RO DU C T IO N Bradykinin is a physiologically and pharmacologically active peptide, consisting of 9 amino acids, and is derived from the kinin group of proteins (Figure 1). Kinins are effectors of vasodilation, vascular permeability, nitric oxide release and arachidonic acid mobilization. They are important regulators of blood pressure, kidney function and heart function, and are also involved in inflammation. Bradykinin causes blood vessels to dilate, and therefore causes a lowering of blood pressure. The ability to measure changes of this peptide hormone with high sensitivity, selectivity and accuracy, as a function of disease progression or drug treatment is thus highly advantageous. Although biologics have historically been quantified using ligand binding assays (LBAs), over the past few years, there has been a trend toward the analysis of large molecules by LC-MS/MS. This is in part driven by the fact that LBAs can suffer from significant cross-reactivity issues and lack of standardization. LC-MS/MS has the advantage of shorter development times, greater accuracy and precision, the ability to multiplex, and can readily distinguish between closely related analogues, metabolites or endogenous interferences. Peptides in general are often difficult to analyze by LC-MS/MS, as MS sensitivity is low due to poor transfer into the gas phase and poor fragmentation, making LC and sample preparation method development challenging. Accurate quantification of bradykinin in plasma is particularly challenging because it is present in low pg/mL levels, is rapidly metabolized, and also artificially produced during blood sampling and sample preparation via proteolytic processes.