GI Norm Mechanism of Action

Pharmacology: Pharmacodynamics: Domperidone is a dopamine antagonist with antiemetic properties. It does not readily cross the blood-brain barrier. Domperidone seldom causes extrapyramidal effects, but it causes a rise in prolactin levels. Its antiemetic effect may be due to a combination of peripheral (gastrokinetic) effects and antagonism of central dopamine receptors in the chemoreceptor trigger zone, which lies outside the blood-brain barrier in the area postrema.
Studies in humans have shown oral domperidone to increase lower esophageal pressure, improve antroduodenal motility and accelerate gastric emptying. Domperidone has no effect on gastric secretion.
Pharmacokinetics: Domperidone is rapidly absorbed after oral administration, with peak plasma concentrations (C_max) occurring at approximately 30 to 60 minutes after dosing in fasted individuals. The C_max and area under the curve (AUC) values of domperidone increase proportionally with dose in the 10 to 20 mg dose range. A 2- to 3-fold accumulation of domperidone AUC was observed with repeated four times a day (every 5 hours) dosing of domperidone for 4 days.
The low absolute bioavailability of oral domperidone (approximately 15%) is due to an extensive first-pass metabolism in the gut wall and liver. Although domperidone's bioavailability is enhanced in normal subjects when taken after a meal, patients with gastrointestinal complaints should take domperidone 15 to 30 minutes before a meal. Reduced gastric acidity impairs the absorption of domperidone. Oral bioavailability is decreased by prior concomitant administration of cimetidine and sodium bicarbonate. The time of peak absorption is slightly delayed and the AUC somewhat increased when the oral drug is taken after a meal.
Oral domperidone does not appear to accumulate or induce its own metabolism; a peak plasma level after 90 minutes of 21 ng/mL after two weeks' oral administration of 30 mg per day was almost the same as that of 18 ng/mL after the first dose. Domperidone is approximately 91 to 93% bound to plasma proteins. Distribution studies with radiolabelled drug in animals have shown wide tissue distribution but low brain concentration. Small amounts of the drug cross the placenta in rats.
Domperidone undergoes rapid and extensive hepatic metabolism by hydroxylation and N-dealkylation.
The plasma half-life of domperidone is 7 to 9 hours after a single oral dose in healthy subjects but is prolonged in patients with severe renal insufficiency. Urinary and fecal excretions amount to 31 and 66% of the oral dose, respectively. The proportion of the drug excreted unchanged is small, i.e., 10% of fecal excretion and approximately 1% of urinary excretion.
Special Populations: Hepatic Impairment: In subjects with moderate hepatic impairment (Pugh score 7 to 9, Child-Pugh rating B), the AUC and C_max of domperidone is 2.9- and 1.5-fold higher, respectively, than in healthy subjects. The unbound fraction is increased by 25%, and the terminal elimination half-life is prolonged from 15 to 23 hours. Subjects with mild hepatic impairment have a somewhat lower systemic exposure than healthy subjects based on C_max and AUC, with no change in protein binding or terminal half-life. Subjects with severe hepatic impairment were not studied.
Renal Impairment: In subjects with severe renal insufficiency (creatinine clearance <30mL/min/1.73m²) the elimination half-life of domperidone is increased from 7.4 to 20.8 hours, but plasma drug levels are lower than in healthy volunteers. Very small amounts of unchanged drug (approximately 1%) are excreted via the kidneys.
Pediatric Patients: No pharmacokinetic data are available in the pediatric population.