Dexloxiglumide is a potent and selective
cholecystokinin type 1 (CCK1) 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. In female patients with
constipation-predominant IBS, clinical efficacy has been demonstrated following administration of
dexloxiglumide 200 mg three times daily.
Dexloxiglumide is rapidly and extensively absorbed after single
oral administration in humans with an absolute bioavailability of 48%. The incomplete bioavailability is due to both incomplete absorption and hepatic first-pass effect. Following multiple-dose administration of 200 mg three times daily, the accumulation is predictable, indicating time-independent pharmacokinetics. In addition,
dexloxiglumide pharmacokinetics are dose-independent after both single and repeated oral three-times-daily doses in the dose range 100-400 mg.
Dexloxiglumide absorption window extends from the jejunum to the colon and the
drug is a substrate and a weak inhibitor of
P-glycoprotein and
multidrug resistance protein 1.
Plasma protein binding of
dexloxiglumide is 94-98% and the
drug has a moderate to low volume of distribution in humans. Systemic clearance of
dexloxiglumide is moderate and
cytochrome P450 (CYP) 3A4/5 and
CYP2C9 have been implicated in the metabolism of
dexloxiglumide to produce O-demethyl dexloxi-glumide. This metabolite is further oxidised to
dexloxiglumide carboxylic acid. These two major metabolites (accounting for up to 50% of
dexloxiglumide elimination) have been identified. However, in human plasma the unchanged
drug represents the major (up to 91%) component of the metabolic profile. The parent
drug is believed to be the major contributor to the efficacy of the compound, since its major metabolites are pharmacologically inactive. In addition, the
drug is a single isomer chiral
drug (eutomer) that does not undergo chiral inversion into its pharmacologically inactive enantiomer (distomer). After
oral administration of (14)C-dexloxiglumide, radioactivity is mainly excreted in bile and in faeces (74% of dose) with much lower excretion in urine (20% of dose). Renal excretion of unchanged
dexloxiglumide is low (7% of dose in urine and faeces, 1% of dose in urine) and is dose-independent in the dose range 100-400 mg. 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. The pharmacokinetics of
dexloxiglumide are also not affected by age, sex and administration with a high-fat breakfast. Mild and moderate liver impairment do not affect the pharmacokinetics of
dexloxiglumide but severe liver impairment causes increases in systemic exposure to
dexloxiglumide and O-demethyl
dexloxiglumide. Thus, the
drug should be prescribed with caution in patients with severe hepatic impairment even though no dose adjustment is warranted. 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.