Disease relevance of Repaglinide

• Repaglinide-induced factitious hypoglycemia [1].
• OBJECTIVE: To compare the effect on glycemic control and weight gain of repaglinide versus metformin combined with bedtime NPH insulin in patients with type 2 diabetes [2].
• CONCLUSIONS: A single dose of repaglinide (0.5-4.0 mg) before breakfast improves insulin secretion and reduces prandial hyperglycemia dose-dependently Administration of repaglinide had no effect on insulin secretion with the second meal, which was consumed 4 h after breakfast [3].
• There was no significant body weight increase in the repaglinide group [4].
• Although adjustment of starting doses of repaglinide is not necessary for renal impairment or renal failure, severe impairment may require more care when upward adjustments of dosage are made [5].

High impact information on Repaglinide

• Nateglinide and repaglinide dose-dependently inhibited whole-cell Kir6.2/SUR1 currents with half-maximal inhibitory concentration (IC(50)) values of 800 and 21 nmol/l, respectively [6].
• These observations suggest that the insulinotropic actions of repaglinide and glibenclamide in vitro and in vivo are secondary to their binding to the high-affinity repaglinide site and that the insulinotropic action of repaglinide involves both distinct and common cellular mechanisms [7].
• Two binding sites were identified: a high-affinity repaglinide (KD = 3.6 nmol/l) site having lower affinity for glibenclamide (14.4 nmol/l) and one high-affinity glibenclamide (25 nmol/l) site having lower affinity for repaglinide (550 nmol/l) [7].
• The insulinotrope repaglinide is successful in therapy, but has been reported to inhibit the recombinant K(ATP) channels of beta cells, cardiocytes and non-vascular smooth muscle cells with similar potencies, suggesting that the (patho-)physiological role of the cardiovascular K(ATP) channels may be overstated [8].
• To this end new short-acting enhancers of insulin secretion such as repaglinide (benzoic acid derivative) and nateglinide (amino acid derivative) have been developed [9].

Chemical compound and disease context of Repaglinide

• Coadministration of cyclosporine may enhance the blood glucose-lowering effect of repaglinide and increase the risk of hypoglycemia [10].
• Over the course of the study, 15% of the repaglinide-treated and 13% of glyburide-treated subjects withdrew due to adverse events, mostly hyperglycemia [11].
• To evaluate the differential ability of both sulfonylureas and meglitinides to stimulate insulin release at modest hypoglycemia, we evaluated dextrose infusion rates necessary to maintain plasma glucose after oral administration of repaglinide (1 mg) or glipizide (5 mg) at euglycemia and again at modest hypoglycemia [12].
• CONCLUSIONS: Telithromycin increases the plasma concentrations and blood glucose-lowering effect of repaglinide by inhibiting its CYP3A4-catalyzed biotransformation and may increase the risk of hypoglycemia [13].
• In alphaTC1-9 glucagonoma cells addition of nateglinide, but not repaglinide, was associated with stimulation of glucagon secretion [14].

Biological context of Repaglinide

• Pharmacokinetics of repaglinide in subjects with renal impairment [5].
• Repaglinide significantly decreased the 5-h glucose AUC (P = 0.03) [15].
• CONCLUSIONS: Repaglinide administration, through good control of postprandial glucose levels, improves brachial reactivity and declines oxidative stress indexes [16].
• In subjects with the CYP2C8*1/*3 genotype, the AUC(0-infinity) and Cmax of repaglinide were 48% and 44% lower, respectively, than in those with the CYP2C8*1/*1 genotype (P < .05) [17].
• CONCLUSIONS: Genetic polymorphism in SLCO1B1 is a major determinant of interindividual variability in the pharmacokinetics of repaglinide [17].

Anatomical context of Repaglinide

• In cell-attached membrane patches of newborn rat islet cells repaglinide (10 nmol/l) and glibenclamide (20 nmol/l) decrease the open probability of single ATP-sensitive K(+)-channels to approximately 10% of the activity prior to addition of the drugs in short-term experiments (< 5 min) [18].
• Effect of repaglinide on cloned beta cell, cardiac and smooth muscle types of ATP-sensitive potassium channels [19].
• AIMS/HYPOTHESIS: The carbamoylbenzoic acid derivative repaglinide is a potent short-acting insulin secretagogue that acts by closing ATP-sensitive potassium (KATP) channels in the plasma membrane of the pancreatic beta cell [19].
• We also used inside-out macropatches excised from Xenopus oocytes for detailed analysis of repaglinide action [19].
• The effect of cyclosporine on repaglinide metabolism was studied in human liver microsomes in vitro [10].

Associations of Repaglinide with other chemical compounds

• OBJECTIVE: This multicenter open-label clinical trial compared the efficacy and safety of repaglinide/troglitazone combination therapy, repaglinide monotherapy, and troglitazone monotherapy in type 2 diabetes that had been inadequately controlled by sulfonylureas, acarbose, or metformin alone [20].
• Cyclosporine had no significant effect on the elimination half-life or renal clearance of repaglinide [10].
• Unexpectedly, montelukast has no significant effect on repaglinide pharmacokinetics, suggesting that it does not significantly inhibit CYP2C8 in vivo [13].
• In contrast to previous estimates based on in vitro CYP2C8 inhibition data, montelukast had no significant effect on the pharmacokinetics of repaglinide or its metabolites and did not significantly alter the effect of telithromycin on repaglinide pharmacokinetics [13].
• OBJECTIVE: Our objective was to study the effects of the macrolide antibiotic clarithromycin on the pharmacokinetics and pharmacodynamics of repaglinide, a novel short-acting antidiabetic drug [21].

Gene context of Repaglinide

• BACKGROUND AND OBJECTIVE: The antidiabetic repaglinide is metabolized by cytochrome P450 (CYP) 2C8 and CYP3A4 [13].
• The pharmacokinetics of repaglinide was not associated with the studied ABCB1 SNPs or the CYP3A5*3 allele [17].
• Blockers of Kir6.2/SUR1 channels, e.g. glibenclamide and repaglinide stimulate release of insulin and are used for treatment of type 2 diabetes [22].
• The effect of SLCO1B1 polymorphism on the pharmacokinetics of repaglinide may be clinically important [17].
• Kir6.2-dependent high-affinity repaglinide binding to beta-cell K(ATP) channels [23].

Analytical, diagnostic and therapeutic context of Repaglinide

• For patients receiving repaglinide, the optimal dose was determined during a 4- to 8-week titration and continued for a 3-month maintenance period [24].
• Optimizing insulin secretagogue therapy in patients with type 2 diabetes: a randomized double-blind study with repaglinide [25].
• Hemodialysis did not significantly affect repaglinide clearance [5].
• In clinical trials of up to 1-year's duration, repaglinide maintained or improved glycaemic control in patients with type 2 diabetes mellitus [26].
• Nateglinide and KAD-1229 clearly stimulate biphasic insulin secretion in vitro and in vivo and their effects are rapidly reversible, whereas the effects of repaglinide and BTS 67 582 are prolonged well beyond their removal from perfusion media in vitro or their clearance in vivo [27].

References