The aim of the study was to investigate the effects of a dipeptidyl peptidase-4 (DPP-4) inhibitor, of metformin, and of the combination of the two agents, on incretin hormone concentrations. Active and inactive (or total) incretin plasma concentrations, plasma DPP-4 activity, and preproglucagon (GCG) gene expression were determined after administration of each agent alone or in combination to mice with diet-induced obesity (DIO) and to healthy human subjects. In mice, metformin increased Gcg expression in the large intestine and elevated the plasma concentrations of inactive glucagon-like peptide 1 (GLP-1) (9-36) and glucagon. In healthy subjects, a DPP-4 inhibitor elevated both active GLP-1 and glucose dependent insulinotropic polypeptide (GIP), metformin increased total GLP-1 (but not GIP), and the combination resulted in additive increases in active GLP-1 plasma concentrations. Metformin did not inhibit plasma DPP-4 activity either in vitro or in vivo. The study results show that metformin is not a DPP-4 inhibitor but rather enhances precursor GCG expression in the large intestine, resulting in increased total GLP-1 concentrations. DPP-4 inhibitors and metformin have complementary mechanisms of action and additive effects with respect to increasing the concentrations of active GLP-1 in plasma.

ABSTRACT:The metabolism and excretion of [ 14 C]sitagliptin, an orally active, potent and selective dipeptidyl peptidase 4 inhibitor, were investigated in humans after a single oral dose of 83 mg/193 Ci. Urine, feces, and plasma were collected at regular intervals for up to 7 days. The primary route of excretion of radioactivity was via the kidneys, with a mean value of 87% of the administered dose recovered in urine. Mean fecal excretion was 13% of the administered dose. Parent drug was the major radioactive component in plasma, urine, and feces, with only 16% of the dose excreted as metabolites (13% in urine and 3% in feces), indicating that sitagliptin was eliminated primarily by renal excretion. Approximately 74% of plasma AUC of total radioactivity was accounted for by parent drug. Six metabolites were detected at trace levels, each representing <1 to 7% of the radioactivity in plasma. These metabolites were the N-sulfate and N-carbamoyl glucuronic acid conjugates of parent drug, a mixture of hydroxylated derivatives, an ether glucuronide of a hydroxylated metabolite, and two metabolites formed by oxidative desaturation of the piperazine ring followed by cyclization. These metabolites were detected also in urine, at low levels. Metabolite profiles in feces were similar to those in urine and plasma, except that the glucuronides were not detected in feces. CYP3A4 was the major cytochrome P450 isozyme responsible for the limited oxidative metabolism of sitagliptin, with some minor contribution from CYP2C8.

Treatment with L-796568 for 28 d had no major lipolytic or thermogenic effect but it lowered triacylglycerol concentrations. This lack of chronic effect on energy balance is likely explained by insufficient recruitment of beta(3)-responsive tissues in humans, down-regulation of the beta(3)-adrenergic receptor-mediated effects with chronic dosing, or both.

Adipocyte complement-related protein of 30 kDa (Acrp30, adiponectin, or AdipoQ) is a fat-derived secreted protein that circulates in plasma. Adipose tissue expression of Acrp30 is lower in insulin-resistant states and it is implicated in the regulation of in vivo insulin sensitivity. Here we have characterized the ability of PPARgamma agonists to modulate Acrp30 expression. After chronic treatment of obese-diabetic (db/db) mice with PPARgamma agonists (11 d), mean plasma Acrp30 protein levels increased (>3x). Similar effects were noted in a nongenetic type 2 diabetes model (fat-fed and low-dose streptozotocin-treated mice). In contrast, treatment of mice (db/db or fat-fed) with metformin or a PPARalpha agonist did not affect plasma Acrp30 protein levels. In a cohort of normal human subjects, 14-d treatment with rosiglitazone also produced a 130% increase in circulating Acrp30 levels vs. placebo. In addition, circulating Acrp30 levels were suppressed 5-fold in patients with severe insulin resistance in association with dominant-negative PPARgamma mutations. Thus, induction of adipose tissue Acrp30 expression and consequent increases in circulating Acrp30 levels represents a novel potential mechanism for PPARgamma-mediated enhancement of whole-body insulin sensitivity. Furthermore, Acrp30 is likely to be a biomarker of in vivo PPARgamma activation.

Renal impairment (RI) is known to influence the pharmacokinetics of nonrenally eliminated drugs, although the mechanism and clinical impact is poorly understood. We assessed the impact of RI and single dose oral rifampin (RIF) on the pharmacokinetics of CYP3A, OATP1B, P‐gp, and BCRP substrates using a microdose cocktail and OATP1B endogenous biomarkers. RI alone had no impact on midazolam (MDZ), maximum plasma concentration (Cmax), and area under the curve (AUC), but a progressive increase in AUC with RI severity for dabigatran (DABI), and up to ~2‐fold higher AUC for pitavastatin (PTV), rosuvastatin (RSV), and atorvastatin (ATV) for all degrees of RI was observed. RIF did not impact MDZ, had a progressively smaller DABI drug‐drug interaction (DDI) with increasing RI severity, a similar 3.1‐fold to 4.4‐fold increase in PTV and RSV AUC in healthy volunteers and patients with RI, and a diminishing DDI with RI severity from 6.1‐fold to 4.7‐fold for ATV. Endogenous biomarkers of OATP1B (bilirubin, coproporphyrin I/III, and sulfated bile salts) were generally not impacted by RI, and RIF effects on these biomarkers in RI were comparable or larger than those in healthy volunteers. The lack of a trend with RI severity of PTV and several OATP1B biomarkers, suggests that mechanisms beyond RI directly impacting OATP1B activity could also be considered. The DABI, RSV, and ATV data suggest an impact of RI on intestinal P‐gp, and potentially BCRP activity. Therefore, DDI data from healthy volunteers may represent a worst‐case scenario for clinically derisking P‐gp and BCRP substrates in the setting of RI.