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Introduction
Dipeptidyl peptidase-4 (DPP-4) inhibitors improve glycemic control in patients with type 2 diabetes mellitus (T2DM) by increasing circulating levels of incretins, endogenous gut-derived peptide hormones that enhance insulin secretion and suppress glucagon release in a glucose-dependent manner [1–4]. Several DPP-4 inhibitors are widely approved for use as oral antihyperglycemic agents in treating patients with T2DM. All have been shown to provide significant improvements in standard indices of glycemic control [5]. There may be important differences between them, however, in the extent to which they provide sustained pharmacodynamic (PD) action (DPP-4 inhibition) throughout their recommended dosing cycles. The existing PD data on these agents have come from separate studies in which each agent was evaluated individually, with different study populations and dosing regimens (single versus multiple dose administration) [6–11]. There is a need, therefore, for comparison of levels of DPP-4 inhibition between different agents within a single study in which conditions are standardized. There also is a need to minimize the impact of dilution and substrate competition artifacts that may be introduced in the process of assaying DPP-4 inhibition ex vivo [9, 11–14] and prevent meaningful comparison between agents even when tested in parallel within the same study.
Reagent solutions must be added to plasma in order to assay DPP-4 activity. As a result, plasma drug concentrations will be lower in an ex vivo assay than they are in vivo and this dilution effect may lead to underestimation of levels of DPP-4 inhibition. The impact of this effect will vary depending on the rate at which a DPP-4 inhibitor dissociates from its binding site on the enzyme, the amount of plasma dilution, and the length of time between the addition of reagents and the measurement of enzyme activity. In addition, there is the potential for ex vivo underestimation of DPP-4 inhibition due to substrate competition. If inhibition is assessed with substrate present at a level that saturates the enzyme, then competitive DPP-4 inhibitors are likely to appear to be less effective than they are under physiological conditions in vivo, where endogenous substrates are likely to be present at subsaturating concentrations.
Measurement of DPP-4 inhibition by sitagliptin is expected to be especially sensitive to these two artifacts because binding between sitagliptin and DPP-4 is competitive and...