Disease relevance of Dexloxiglumide

• CCK is a major mediator of the sensitisation of gastric perception by lipids in patients with functional dyspepsia as the CCK-A receptor antagonist dexloxiglumide markedly diminishes this effect [1].
• Dexloxiglumide is a potent and selective cholecystokinin type 1 (CCK(1)) receptor antagonist currently under development in a variety of diseases affecting the gastrointestinal tract such as gastro-oesophageal reflux disease, irritable bowel syndrome (IBS), functional dyspepsia, constipation and gastric emptying disorders [2].
• As the kidney is a minor contributor to the elimination of dexloxiglumide and/or its metabolites in humans, the pharmacokinetics of the drug should not be affected in patients with renal insufficiency [2].
• The CCK-induced pancreatic hypertrophy and hyperplasia are blocked by the potent and specific CCK(A)-receptor antagonist, dexloxiglumide [3].
• AIMS: Dexloxiglumide is a new CCK(1) receptor antagonist under investigation for treatment of functional gastrointestinal disorders and is metabolized by CYP3A4 and CYP2C9 [4].

High impact information on Dexloxiglumide

• The pharmacokinetics of dexloxiglumide are also not affected by age, sex and administration with a high-fat breakfast [2].
• The results of different drug interaction studies have indicated that no clinically relevant metabolic and concomitant drug-drug interactions are expected during the clinical use of dexloxiglumide [2].
• Plasma protein binding of dexloxiglumide is 94-98% and the drug has a moderate to low volume of distribution in humans [2].
• Dexloxiglumide is rapidly and extensively absorbed after single oral administration in humans with an absolute bioavailability of 48% [2].
• CONCLUSIONS: Dexloxiglumide accelerates gastric emptying and delays proximal but not overall CT in patients with C-IBS [5].

Biological context of Dexloxiglumide

• Fluconazole coadministration resulted in a 2.5-fold increase (90% CI 235-267) in dexloxiglumide AUC, 40% increase (90% CI 136-156) in ODM AUC and an 18% decrease (90% CI 82-94) in DCA AUC [4].
• Characterization of dexloxiglumide in vitro biopharmaceutical properties and active transport [6].
• The data were consistent with biliary excretion and perhaps some enterohepatic circulation of conjugates of dexloxiglumide and at least one of its metabolites [7].
• LC-MS/MS showed that dexloxiglumide was metabolised mainly by hydroxylation in the N-(3-methoxypropyl)pentyl sidechain and by O-demethylation followed by subsequent oxidation of the resulting alcohol to a carboxylic acid [8].
• At present, dexloxiglumide is in an advanced stage of clinical research in gastroenterology [9].

Anatomical context of Dexloxiglumide

• RESULTS: Dexloxiglumide was associated with accelerated gastric emptying t(1/2) (p= 0.004), and slower ascending colon emptying t(1/2) (p < 0.01), with no significant effect on overall CT or satisfactory relief of IBS [5].
• Dexloxiglumide was effluxed from MRP1-NIH3T3 cells (NIH-3T3 cells expressing the multidrug resistance-associated protein 1) [6].
• The aim of this study was to evaluate the effect of dexloxiglumide on isolated human gallbladder contraction induced by cholecystokinin-octapeptide and to compare this effect to that of lorglumide and amiglumide, two glutaramic acid analogs of dexloxiglumide [10].
• Effect of a new CCK-A receptor antagonist, dexloxiglumide, on the exocrine pancreas in the rat [11].
• These results demonstrate the ability of dexloxiglumide to antagonize the effects of CCK on pancreatic secretion and growth, suggesting that this compound is a potent and selective antagonist of CCK-A-receptors in the pancreas [11].

Associations of Dexloxiglumide with other chemical compounds

• On the other hand, dexloxiglumide, at doses able to almost completely block CCKA mediated effects (i.e. delay of gastric emptying), was ineffective against pentagastrin-induced acid hypersecretion [12].
• The geometric mean ratios (GMRs, dexloxiglumide/placebo) of the plasma concentration-time curve over 24 hours with corresponding 90% confidence intervals (CIs) for EE and 17-DNE were 1.21 (1.17-1.26) and 0.92 (0.89-0.95), respectively [13].
• Drugs acting at motilin (erythromycin) and cholecystokinin-1 (dexloxiglumide) receptors accelerate gastric emptying [14].
• Rhodamine 123 efflux was reduced by dexloxiglumide from 4.06 (+/-0.34) to 2.84 (+/-0.15) across Caco-2 monolayers, and from 17.3 (+/-0.9) to 8.26 (+/-1.38) across MDR1-MDCK monolayers, further indicating dexloxiglumide interaction with P-gp [6].
• Loxiglumide (and its dextroisomer, dexloxiglumide) is the only CCKA receptor antagonist that is being evaluated clinically [15].

Gene context of Dexloxiglumide

• Dexloxiglumide has a potent antagonistic effect, of a competitive nature, on human gallbladder cholecystokinin type 1 receptors [9].
• CCK1 receptor antagonist, dexloxiglumide: effects on human isolated gallbladder. Potential clinical applications [9].
• Interaction of dexloxiglumide, a cholecystokinin type-1 receptor antagonist, with human cytochromes P450 [16].
• The transport of dexloxiglumide across MDR1-MDCK (P-gp overexpressing Madine Darby canine kidney cells) monolayers was polarized, with a BL-AP/AP-BL permeability ratio of 9.35 (+/-0.73), which was reduced to 1.03 (+/-0.03) by P-gp inhibition [6].
• In vitro, dexloxiglumide was moderately modulated by P-gp and MRP1, which provides a rationale for the design of drug interaction studies [6].

Analytical, diagnostic and therapeutic context of Dexloxiglumide

• AIMS: To evaluate the effects of dexloxiglumide, a CCK-1 receptor antagonist, on gastrointestinal transit (GIT) and symptoms in patients with constipation-predominant IBS (C-IBS); and to explore the influence of CCK-1 receptor polymorphisms on gut transit and the pharmacodynamic response to therapy [5].
• Dexloxiglumide plasma and urinary concentration, determined using validated HPLC methods with UV detection, were used for the pharmacokinetic analysis by standard noncompartmental methods [17].
• SUBJECTS AND METHODS: Twelve volunteers were enrolled in the present study and received orally 100, 200 and 400 mg of dexloxiglumide as tablets as a single dose followed by repeated t.i.d. doses for 7 days according to a randomized, double-blind, double-dummy complete crossover design [17].
• However, by April 2002 its development for indications other than acute and chronic pancreatitis had been discontinued in favor of the D-enantiomer, dexloxiglumide [449509], which is in clinical trials for gastrointestinal disorders [370620] [18].

References