Aldosterone release in isolated rat glomerular zona perfused cells is stimulated by metoclopramide (0.01-10 μM) [3]. Acetylcholine (ACh) is released from intrinsic cholinergic motor neurons through four mechanisms that metoclopramide causes: inhibition of presynaptic D2 receptors, stimulation of presynaptic excitatory 5-HT4 receptors, inhibition of D2 postsynaptic receptors, and antagonism of presynaptic inhibition of muscarinic receptors, which leads to an additional increase in acetylcholine release [2].

Throughout the whole estrous cycle, metoclopramide (6.7 µg/g; daily subcutaneous injection for 50 days) dramatically raises pituitary prolactin cell volume and quantity [4]. Mice treated intraperitoneally with metoclopramide (5–40 mg/kg) exhibit catalepsy and are less likely to climb their cages in response to apomorphine [5]. Mice that receive an intraperitoneal dose of metoclopramide (1.25–2.5 mg/kg) may exhibit a stereotypical behavior of climbing cages [5].

Animal/Disease Models: Adult female mice of Swiss EPM-1 strain [4]
Doses: 6.7 µg/g
Route of Administration: daily subcutaneous injection for 50 days
Experimental Results: Increased the amount of prolactin and also stimulated its metabolic activity.

Absorption, Distribution and Excretion
Metoclopramide is rapidly absorbed in the gastrointestinal tract with an absorption rate of about 84%. The bioavailability of the oral preparation is reported to be about 40.7%, but can range from 30-100%. Nasal metoclopramide is 47% bioavailable. A 15mg dose reaches a Cmax of 41.0 ng/mL, with a Tmax of 1.25 h, and an AUC of 367 ng\*h/mL.
About 85% of an orally administered dose was measured in the urine within 72 hours during a pharmacokinetic study. An average of 18% to 22% of 10-20 mg dose was recovered as free drug within 3 days of administration.
The volume of distribution of metoclopramide is approximately 3.5 L/kg. This implies a high level of tissue distribution. Metoclopramide crosses the placental barrier and can cause extrapyramidal symptoms in the fetus.
The renal clearance of metoclopramide is 0.16 L/h/kg with a total clearance of 0.7 L/h/kg. Clinical studies showed that the clearance of metoclopramide may be reduced by up to 50% in patients with renal impairment. After high intravenous doses, total metoclopramide clearance ranged from 0.31 to 0.69 L/kg/h.
Metoclopramide is rapidly and almost completely absorbed from the GI tract following oral administration; however, absorption may be delayed or diminished in patients with gastric stasis. Considerable interindividual variations (up to fivefold) in peak plasma concentration have been reported with the same oral dose of metoclopramide. This variability apparently results from interindividual differences in first-pass metabolism of the drug.
Bioavailability of metoclopramide appears to correlate with the ratio of free:conjugated metoclopramide concentrations in urine. It appears that sulfate conjugation in the GI lumen and/or during first pass through the liver is the principal determinant of bioavailability of orally administered metoclopramide. The absolute bioavailability of orally administered metoclopramide has not been clearly established in humans, but limited data indicate that 30-100% of an oral dose of the drug reaches systemic circulation as unchanged metoclopramide. Following IM administration, the absolute bioavailability of metoclopramide is 74-96%.
Following oral administration of a single 10-mg dose of the drug in healthy, fasting adults in one study, peak plasma metoclopramide concentrations of 32-44 ng/mL occurred at 1-2 hours; following oral administration of a single 20-mg dose, peak plasma metoclopramide concentrations of 72-87 ng/mL occurred at an average of 2 hours.
In a study in infants (3.5 weeks-5.4 months of age) with gastroesophageal reflux who received 0.15-mg/kg oral doses of metoclopramide every 6 hours for 10 doses as an oral solution, the mean peak plasma concentration (56.8 ng/mL) of the drug after the 10th dose was twofold higher compared with that after the first dose (29 ng/mL), suggesting that metoclopramide accumulates in plasma following multiple oral dosing in this age group. In these patients, time to reach mean peak plasma concentrations (2.2 hours) was similar after the 10th dose to that occurring after the first dose.
For more Absorption, Distribution and Excretion (Complete) data for Metoclopramide (18 total), please visit the HSDB record page.

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Metabolism / Metabolites
Metoclopramide undergoes first-pass metabolism and its metabolism varies according to the individual. This drug is metabolized by cytochrome P450 enzymes in the liver. CYP2D6 and CYP3A4 both contribute to its metabolism, with CYP2D6 being more heavily involved. CYP1A2 is also a minor contributing enzyme. The process of N-4 sulphate conjugation is a primary metabolic pathway of metoclopramide.
Although the exact metabolic fate of metoclopramide is not clearly established, it appears that metoclopramide is only minimally metabolized. The major metabolite found in urine is 2-[(4-amino-5-chloro-2-methoxybenzoyl)amino]acetic acid; it is not known if this metabolite is pharmacologically active. Metoclopramide is conjugated with sulfuric and/or glucuronic acid.
Metoclopramide has known human metabolites that include monodeethylmetoclopramide.

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Biological Half-Life
The mean elimination half-life of metoclopramide in people with healthy renal function ranges from 5 to 6 hours but is prolonged in patients with renal impairment. Downward dose adjustment should be considered.
In adults, the half-life of metoclopramide in the initial phase (t1/2 alpha) is about 5 minutes, and the half-life in the terminal phase (t1/2 beta) ranges from 2.5-6 hours. In children receiving oral or IV metoclopramide, the elimination half-life of the drug reportedly is 4.1-4.5 hours. Following oral administration of 0.15-mg/kg doses of metoclopramide every 6 hours for 10 doses in an infant (3.5 weeks of age), elimination half-lives of 23.1 and 10.3 hours were observed after the first and 10th dose, respectively, which were substantially longer than those reported in older infants, suggesting a reduced clearance in the neonate possibly being associated with immature renal and hepatic functions present at birth.

Interactions
The effects of metoclopramide on gastrointestinal motility are antagonized by anticholinergic drugs and narcotic analgesics. Additive sedative effects can occur when metoclopramide is given with alcohol, sedatives, hypnotics, narcotics, or tranquilizers.
The finding that metoclopramide releases catecholamines in patients with essential hypertension suggests that it should be used cautiously, if at all, in patients receiving monoamine oxidase inhibitors.
Absorption of drugs from the stomach may be diminished (e.g., digoxin) by metoclopramide, whereas the rate and/or extent of absorption of drugs from the small bowel may be increased (e.g., acetaminophen, tetracycline, levodopa, ethanol, cyclosporine).
Gastroparesis (gastric stasis) may be responsible for poor diabetic control in some patients. Exogenously administered insulin may begin to act before food has left the stomach and lead to hypoglycemia. Because the action of metoclopramide will influence the delivery of food to the intestines and thus the rate of absorption, insulin dosage or timing of dosage may require adjustment.
For more Interactions (Complete) data for Metoclopramide (10 total), please visit the HSDB record page.

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Non-Human Toxicity Values
LD50 Rat oral 750 mg/kg
LD50 Rat ip 114 mg/kg
LD50 Rat sc 340 mg/kg
LD50 Rat iv 50 mg/kg
For more Non-Human Toxicity Values (Complete) data for Metoclopramide (8 total), please visit the HSDB record page.

[1]. Synthesis and structure-activity relationships of 4-amino-5-chloro-N-(1,4-dialkylhexahydro-1,4-diazepin-6-yl)-2-methoxybenzamide derivatives, novel and potent serotonin 5-HT3 and dopamine D2 receptors dual antagonist. Chem Pharm Bull (.

[2]. Review article: metoclopramide and tardive dyskinesia. Aliment Pharmacol Ther. 2010 Jan;31(1):11-9.

[3]. In vivo and in vitro studies on the effect of metoclopramide on aldosterone secretion. Clin Endocrinol (Oxf). 1980 Jul;13(1):45-50.

[4]. Dose-dependent response of central dopaminergic systems to metoclopramide in mice. Indian J Exp Biol. 1997 Jun;35(6):618-22.

[5]. Effects of metoclopramide on the mouse anterior pituitary during the estrous cycle. Clinics (Sao Paulo). 2011;66(6):1101-4.

Therapeutic Uses
Antiemetics; Dopamine Antagonists
Metoclopramide tablets are indicated as short-term (4 to 12 weeks) therapy for adults with symptomatic, documented gastroesophageal reflux who fail to respond to conventional therapy. /Included in US product label/
Metoclopramide tablets, USP is indicated for the relief of symptoms associated with acute and recurrent diabetic gastric stasis. The usual manifestations of delayed gastric emptying (eg, nausea, vomiting, heartburn, persistent fullness after meals, and anorexia) appear to respond to Metoclopramide Tablets within different time intervals. Significant relief of nausea occurs early and continues to improve over a three-week period. Relief of vomiting and anorexia may precede the relief of abdominal fullness by one week or more. /Included in US product label/
Metoclopramide injection is indicated for the prophylaxis of vomiting associated with emetogenic cancer chemotherapy. /Included in US product label/
For more Therapeutic Uses (Complete) data for Metoclopramide (8 total), please visit the HSDB record page.

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Drug Warnings
WARNING: TARDIVE DYSKINESIA-Treatment with metoclopramide can cause tardive dyskinesia, a serious movement disorder that is often irreversible. The risk of developing tardive dyskinesia increases with duration of treatment and total cumulative dose. Metoclopramide therapy should be discontinued in patients who develop signs or symptoms of tardive dyskinesia. There is no known treatment for tardive dyskinesia. In some patients, symptoms may lessen or resolve after metoclopramide treatment is stopped. Treatment with metoclopramide for longer than 12 weeks should be avoided in all but rare cases where therapeutic benefit is thought to outweigh the risk of developing tardive dyskinesia.
Adverse reactions to metoclopramide generally involve the CNS and GI tract and are usually mild, transient, and reversible following discontinuance of the drug. In general, the incidence of metoclopramide-induced adverse effects is related to dosage and duration of therapy.
The most frequent adverse effects of metoclopramide involve the CNS. Restlessness, drowsiness, fatigue, and lassitude have been reported in patients receiving the drug; these effects occur in about 10% of patients receiving a dosage of 10 mg 4 times daily. Insomnia, headache, confusion, dizziness, or depression with suicidal ideation occurs less frequently. The risk of drowsiness is increased at higher doses, occurring in about 70% of patients receiving doses of 1-2 mg/kg. Seizures have been reported rarely, although a causal relationship to metoclopramide has not been established. Hallucinations also have been reported rarely. Feelings of anxiety or agitation also may occur, especially following rapid IV injection of the drug.
Extrapyramidal reactions (eg, acute dystonic reactions, akathisia) may occur in patients receiving metoclopramide and apparently are mediated via blockade of central dopaminergic receptors involved in motor function. Although extrapyramidal reactions may occur in all age groups and at any dose, they occur more frequently in pediatric patients and adults younger than 30 years of age and following IV administration of high doses of the drug (eg, those used in prophylaxis of cancer chemotherapy-induced vomiting). Extrapyramidal reactions generally occur within 24-48 hours after starting therapy and usually subside within 24 hours following discontinuance of the drug.
For more Drug Warnings (Complete) data for Metoclopramide (31 total), please visit the HSDB record page.

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Pharmacodynamics
Metoclopramide increases gastric emptying by decreasing lower esophageal sphincter (LES) pressure. It also exerts effects on the area postrema of the brain, preventing and relieving the symptoms of nausea and vomiting. In addition, this drug increases gastrointestinal motility without increasing biliary, gastric, or pancreatic secretions. Because of its antidopaminergic activity, metoclopramide can cause symptoms of tardive dyskinesia (TD), dystonia, and akathisia, and should therefore not be administered for longer than 12 weeks.

C14H22CLN3O2

299.7964

299.14

364-62-5

Metoclopramide hydrochloride hydrate;54143-57-6;Metoclopramide hydrochloride;7232-21-5

4168

White to off-white solid powder

1.2±0.1 g/cm3

454.8±55.0 °C at 760 mmHg

146-148°C

228.9±31.5 °C

0.0±1.2 mmHg at 25°C

1.545

3.1

2

4

7

20

300

0

TTWJBBZEZQICBI-UHFFFAOYSA-N

InChI=1S/C14H22ClN3O2/c1-4-18(5-2)7-6-17-14(19)10-8-11(15)12(16)9-13(10)20-3/h8-9H,4-7,16H2,1-3H3,(H,17,19)

4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-methoxybenzamide

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: This product requires protection from light (avoid light exposure) during transportation and storage.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~110 mg/mL (~366.91 mM)

Solubility in Formulation 1: ≥ 2.75 mg/mL (9.17 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 27.5 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.75 mg/mL (9.17 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 27.5 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)