Pharmacokinetic, pharmacodynamic, and efficacy profiles of alogliptin, a novel inhibitor of dipeptidyl peptidase-4, in rats, dogs, and monkeys

Lee, Bumsup; Shi, Lihong; Kassel, Daniel B.; Asakawa, Takeshi; Takeuchi, Koji; Christopher, Ronald J.

doi:10.1016/j.ejphar.2008.04.047

Cited by 86 publications

(60 citation statements)

References 33 publications

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“…Preliminary experiments showed that 3 mg/kg of alogliptin is required to effectively inhibit DPP4. Maximum inhibition (Ն98%) was maintained 15 min after administration, and effective inhibition (Ͼ65%) lasted at least 12 h (27).…”

Section: Methodsmentioning

confidence: 99%

An interaction between glucagon-like peptide-1 and adenosine contributes to cardioprotection of a dipeptidyl peptidase 4 inhibitor from myocardial ischemia-reperfusion injury

Ihara

Asanuma

Yamazaki

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

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zuki N, Kitakaze M. An interaction between glucagon-like peptide-1 and adenosine contributes to cardioprotection of a dipeptidyl peptidase 4 inhibitor from myocardial ischemia-reperfusion injury. Am J Physiol Heart Circ Physiol 308: H1287-H1297, 2015. First published March 7, 2015; doi:10.1152/ajpheart.00835.2014.-Dipeptidyl peptidase 4 (DPP4) inhibitors suppress the metabolism of the potent antihyperglycemic hormone glucagon-like peptide-1 (GLP-1). DPP4 was recently shown to provide cardioprotection through a reduction of infarct size, but the mechanism for this remains elusive. Known interactions between DPP4 and adenosine deaminase (ADA) suggest an involvement of adenosine signaling in DPP4 inhibitor-mediated cardioprotection. We tested whether the protective mechanism of the DPP4 inhibitor alogliptin against myocardial ischemia-reperfusion injury involves GLP-1-and/or adenosine-dependent signaling in canine hearts. In anesthetized dogs, the coronary artery was occluded for 90 min followed by reperfusion for 6 h. A 4-day pretreatment with alogliptin reduced the infarct size from 43.1 Ϯ 2.5% to 17.1 Ϯ 5.0% without affecting collateral flow and hemodynamic parameters, indicating a potent antinecrotic effect. Alogliptin also suppressed apoptosis as demonstrated by the following analysis: 1) reduction in the Bax-to-Bcl2 ratio; 2) cytochrome c release, 3) an increase in Bad phosphorylation in the cytosolic fraction; and 4) terminal deoxynucleotidyl transferase dUTP nick end labeling assay. This DPP4 inhibitor did not affect blood ADA activity or adenosine concentrations. In contrast, the nonselective adenosine receptor blocker 8-(p-sulfophenyl)theophylline (8SPT) completely blunted the effect of alogliptin. Alogliptin did not affect Erk1/2 phosphorylation, but it did stimulate phosphorylation of Akt, glycogen synthase kinase-3␤, and cAMP response element-binding protein (CREB). Only 8SPT prevented alogliptin-induced CREB phosphorylation. In conclusion, the DPP4 inhibitor alogliptin suppresses ischemia-reperfusion injury via adenosine receptor-and CREB-dependent signaling pathways. dipeptidyl peptidase 4 inhibitor; ischemia-reperfusion injury; myocardial infarction; cardioprotection; adenosine GLUCAGON-LIKE PEPTIDE-1 (GLP-1) is mostly known as a potent antihyperglycemic hormone secreted by intestinal cells to stimulate glucose-dependent insulin secretion from pancreatic beta cells. Once in circulation, GLP-1 is rapidly metabolized by dipeptidyl peptidase 4 (DPP4). Therefore, GLP-1 analogs and DPP4 inhibitors are commonly prescribed for the treatment of diabetes mellitus (6, 11). DPP4 inhibitors also exert extrapancreatic effects in the brain, stomach, and heart (39). However, the mechanisms by which they mediate these effects remain largely unknown. Several reports showed that DPP4 inhibitors limit the infarct size after ischemia-reperfusion in the heart (15, 51), but the extent of their beneficial effects remains controversial (7,52). Recently, several reports have indicated that DPP4 forms a complex with adenosin...

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Section: Methodsmentioning

confidence: 99%

An interaction between glucagon-like peptide-1 and adenosine contributes to cardioprotection of a dipeptidyl peptidase 4 inhibitor from myocardial ischemia-reperfusion injury

Ihara

Asanuma

Yamazaki

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

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“…This finding may be explained by the differences in selectivity and inhibition activity for DPP-4 between sitagliptin and alogliptin. Actually, alogliptin is reported to have higher selectivity and stronger inhibitory activity for DPP-4 as compared with sitagliptin [15,16]. The powerful DPP-4 inhibition by alogliptin is expected to provide two effects in body.…”

Section: Discussionmentioning

confidence: 99%

“…Allogliptin is a newly-developed DPP-4 inhibitor which has higher selectivity and stronger inhibitory activity for DPP-4 as compared with sitagliptin [15,16]. Considering these properties of allogliptin for the DPP-4 enzyme, we hypothesized that stronger DPP-4 inhibition with this drug on top of angiotensin II type 1 receptor blockade may provide more beneficial effects on incipient DN independent of its glucose-lowering effects.…”

Section: Measurementsmentioning

confidence: 99%

DPP-4 inhibition with alogliptin on top of angiotensin II type 1 receptor blockade ameliorates albuminuria <i>via</i> up-regulation of SDF-1α in type 2 diabetic patients with incipient nephropathy

Fujita

Taniai²,

Murayama³

et al. 2014

Endocr J

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DipeptiDyl peptiDase-4 (DPP-4) inhibitor is a new class of anti-diabetic drug which enhances circulating levels of a gut incretin hormone, glucagon-like peptide-1 (GLP-1), by inhibiting the degradation of GLP-1 [1]. GLP-1 stimulates insulin secretion from pancreatic β-cells in a blood glucose-dependent manner and suppresses glucagon release from pancreatic abstract. Dipeptidyl peptidase-4 (DPP-4) inhibitor is a new class of anti-diabetic drug which exerts its glucose-lowering action by suppressing the degradation of a gut incretin hormone glucagon-like peptide-1 (GLP-1). To elucidate whether treatment with stronger DPP-4 inhibitor on top of angiotensin II type 1 receptor blocker (ARB) provides greater renal protective effects, we performed a crossover study with two DPP-4 inhibitors, sitagliptin and alogliptin, in twelve type 2 diabetic patients with incipient nephropathy taking ARBs. This study consisted of three treatment periods: sitagliptin 50 mg/day for 4 weeks (first period), alogliptin 25 mg/day for 4 weeks (second period), and sitagliptin 50 mg/day for 4 weeks (third period). Significant changes in body mass index, blood pressure, serum lipids, serum creatinine, estimated glomerular filtration rate, and HbA1c were not observed among the three treatment periods. Reduced urinary levels of albumin and an oxidative stress marker 8-hydroxy-2'-deoxyguanosine (8-OHdG), increased urinary cAMP levels, and elevated plasma levels of stromal cell-derived factor-1α (SDF-1α) which is a physiological substrate of DPP-4 were observed after the switch from sitagliptin to a stronger DPP-4 inhibitor alogliptin. Given a large body of evidence indicating anti-oxidative action of cAMP and up-regulation of cellular cAMP production by SDF-1α, the present results suggest that more powerful DPP-4 inhibition on top of angiotensin II type 1 receptor blockade would offer additional protection against early-stage diabetic nephropathy beyond that attributed to glycemic control, via reduction of renal oxidative stress by SDF-1α-cAMP pathway activation.

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“…The disposition of alogliptin has been examined for different levels of the renal function, and the relationship between the level of the renal function and the dose of alogliptin has been clarified. The absence of accumulation has also been shown in simulation experiments, although these studies were based on single-dose administration (15,29). Moreover, in addition to its hypoglycemic effects, the multifaceted extrapancreatic actions, including the improvement of lipid profiles or hypotensive actions mediated by the inhibition of reabsorption of sodium in the kidneys, of alogliptin have been reported, although in a small number of patients (24,30,31).…”

Section: Discussionmentioning

confidence: 99%

Effects of Alogliptin in Chronic Kidney Disease Patients with Type 2 Diabetes

et al. 2014

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Objective Diabetes is a major risk factor for chronic kidney disease (CKD). In this study, we examined the effects of alogliptin on blood glucose control and the renal function in type 2 diabetes CKD patients. Methods We recruited 36 CKD patients with type 2 diabetes. The patients were followed up for six months after adding alogliptin. Blood biochemical, urine test and office BP values were obtained six months before and after the start of treatment. Results The mean HbA1c value was not decreased; however, the 1,5-AG values tended to improve (p= 0.1023). The mean eGFR was unchanged. There were no significant changes in the patients with an eGFR of 60 mL/min/1.73 m 2 or more (25 patients) or in the patients with an eGFR less than 60 mL/min/1.73 m 2 (11 patients). A total of 15 patients were identified to have rapidly declining diabetic nephropathy, with an annual reduction in eGFR of 5 mL/min/1.73 m 2 or more. The slope of the regression line for eGFR (-1.296 before starting treatment with alogliptin) was positive, increasing up to 0.08786. The eGFR values appeared to stop decreasing and positively reversed. The urinary albumin-to-creatinine ratio exhibited a downward trend. The effect on the renal function was independent of the levels of blood sugar, blood pressure and lipids. Conclusion We examined the ability of alogliptin to maintain the renal function in patients with CKD complicated by type 2 diabetes. Our study suggests that alogliptin can be safely administered in patients with CKD. However, although we expected alogliptin to demonstrate renal protective effects, were unable to detect statistically significant differences. One reason for this finding is that there are few registered cases.

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Pharmacokinetic, pharmacodynamic, and efficacy profiles of alogliptin, a novel inhibitor of dipeptidyl peptidase-4, in rats, dogs, and monkeys

Cited by 86 publications

References 33 publications

An interaction between glucagon-like peptide-1 and adenosine contributes to cardioprotection of a dipeptidyl peptidase 4 inhibitor from myocardial ischemia-reperfusion injury

An interaction between glucagon-like peptide-1 and adenosine contributes to cardioprotection of a dipeptidyl peptidase 4 inhibitor from myocardial ischemia-reperfusion injury

DPP-4 inhibition with alogliptin on top of angiotensin II type 1 receptor blockade ameliorates albuminuria <i>via</i> up-regulation of SDF-1α in type 2 diabetic patients with incipient nephropathy

Effects of Alogliptin in Chronic Kidney Disease Patients with Type 2 Diabetes

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