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Simultaneous absolute quantification of the glucose-dependent insulinotropic polypeptides GIP1-42 and GIP3-42 in mouse plasma by LC/ESI-MS/MS: preclinical evaluation of DP-IV inhibitors.

The incretin hormone Glucose-dependent Insulinotropic Polypeptide GIP1-42 (approximately 5 kDa), is released postprandially, and rapidly degraded by Dipeptidyl Peptidase IV (DP-IV) to yield the inactive GIP3-42. Methods for the quantification of the pair of GIP peptides include combinations of immunoassays; however, mass spectrometry based approaches can offer the improved selectivity required for the distinction between the active and inactive forms. In this study, we report an LC/ESI-MS/MS approach for the simultaneous absolute quantification of GIP1-42 and GIP3-42 via the corresponding surrogate proteolytic peptide fragments, GIP1-16 and GIP3-16. These surrogate peptides afford approximately 250-fold improvement in lower limits of quantification (LLOQ) compared to the precursor proteins. The LLOQ of the reported method was 5 ng/mL (5-1000 ng/mL) for GIP1-42 and 10 ng/mL (10-1000 ng/mL) for GIP3-42, using 100 microL of mouse plasma. This is the first reported study in which the GIP1-42 and GIP3-42 polypeptides are quantified simultaneously with LC/ESI-MS/MS via their tryptic surrogate peptides. The approach is suitable for both preclinical and clinical pharmacokinetic studies due to the low volume required for the analysis. The described methodology was applied to a pharmacokinetic study, in which enhanced stability of exogenously administered GIP1-42 was demonstrated in mice treated with a DP-IV inhibitor.