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 from the gastrointestinal tract, with an absorption rate of approximately 84%. The reported bioavailability of oral formulations is approximately 40.7%, but can range from 30% to 100%. The bioavailability of nasal metoclopramide is 47%. The peak plasma concentration (Cmax) of a 15 mg dose is 41.0 ng/mL, the time to peak concentration (Tmax) is 1.25 hours, and the area under the curve (AUC) is 367 ngh/mL. In a pharmacokinetic study, approximately 85% of the oral dose was excreted in the urine within 72 hours. An average of 18% to 22% of the 10–20 mg dose was recovered as free drug within 3 days after administration. The volume of distribution of metoclopramide is approximately 3.5 L/kg, indicating its wide tissue distribution. Metoclopramide can cross the placental barrier and may cause extrapyramidal symptoms in the fetus. The renal clearance of metoclopramide is 0.16 L/h/kg, and the total clearance is 0.7 L/h/kg. Clinical studies have shown that metoclopramide clearance can be reduced by up to 50% in patients with renal insufficiency. After intravenous administration of high-dose metoclopramide, the total clearance ranges from 0.31 to 0.69 L/kg/h. After oral administration, metoclopramide is rapidly and almost completely absorbed in the gastrointestinal tract; however, absorption may be delayed or reduced in patients with gastric retention. Even with the same oral dose of metoclopramide, there are significant individual differences in peak plasma concentrations (up to five-fold). This variability is clearly due to individual differences in first-pass metabolism. The bioavailability of metoclopramide appears to be related to the ratio of free to conjugated metoclopramide concentrations in urine. Sulfate binding during first-pass metabolism in the gastrointestinal tract and/or liver appears to be the primary determinant of the bioavailability of orally administered metoclopramide. The absolute bioavailability of orally administered metoclopramide has not been definitively established in humans, but limited data suggest that 30-100% of orally administered doses enter systemic circulation unchanged. Following intramuscular injection, the absolute bioavailability of metoclopramide is 74-96%. In one study, in healthy fasting adults, a single oral dose of 10 mg metoclopramide resulted in peak plasma concentrations of 32-44 ng/mL, occurring 1-2 hours later; a single oral dose of 20 mg metoclopramide resulted in peak plasma concentrations of 72-87 ng/mL, occurring on average 2 hours later. In a study of infants (3.5 weeks to 5.4 months old) with gastroesophageal reflux disease, these infants were given 0.15 mg/kg metoclopramide solution orally every 6 hours for a total of 10 doses. The mean peak plasma concentration after the 10th dose (56.8 ng/mL) was twice that after the first dose (29 ng/mL), indicating that in this age group, the drug accumulates in plasma after multiple oral doses of metoclopramide. In these patients, the time to reach the mean peak plasma concentration after the 10th dose (2.2 hours) was similar to that after the first dose. For more complete data on the absorption, distribution, and excretion of metoclopramide (18 in total), please visit the HSDB record page. Metabolism/Metabolic Substances Metoclopramide undergoes first-pass metabolism, which varies from person to person. The drug is metabolized in the liver by cytochrome P450 enzymes. Both CYP2D6 and CYP3A4 are involved in its metabolism, with CYP2D6 playing a more significant role. CYP1A2 is also a minor metabolic enzyme. N-4 sulfate conjugation is the major metabolic pathway of metoclopramide. Although the exact metabolic pathway of metoclopramide is not fully understood, its metabolism appears to be low. The major metabolite found in urine is 2-[(4-amino-5-chloro-2-methoxybenzoyl)amino]acetic acid; it is unclear whether this metabolite has pharmacological activity. Metoclopramide is conjugated with sulfate and/or glucuronic acid. Known metabolites of metoclopramide include monodeethylmetoclopramide. Biological Half-Life: The mean elimination half-life of metoclopramide in patients with normal renal function is 5 to 6 hours, but the half-life is prolonged in patients with renal impairment. Dose reduction should be considered. In adults, the initial phase half-life (t1/2α) of metoclopramide is approximately 5 minutes, and the terminal phase half-life (t1/2β) is 2.5 to 6 hours. In children, the elimination half-life of metoclopramide after oral or intravenous administration has been reported to be 4.1–4.5 hours. In a 3.5-week-old infant, after oral administration of 0.15 mg/kg metoclopramide every 6 hours for 10 doses, the elimination half-lives after the first and tenth doses were 23.1 hours and 10.3 hours, respectively, significantly longer than reported values for older infants, suggesting reduced drug clearance in neonates, which may be related to the immature development of renal and hepatic function at birth.

Interactions
Metoclopramide's effects on gastrointestinal motility can be antagonized by anticholinergic drugs and narcotic analgesics. When used in combination with alcohol, sedatives, hypnotics, anesthetics, or tranquilizers, metoclopramide can produce an additive sedative effect. Metoclopramide can promote the release of catecholamines in patients with essential hypertension; therefore, it should be used with caution, or even avoided, in patients taking monoamine oxidase inhibitors. Metoclopramide can reduce gastric absorption of certain drugs (e.g., digoxin) while increasing the rate and/or extent of small intestinal absorption of certain drugs (e.g., acetaminophen, tetracycline, levodopa, ethanol, cyclosporine). Gastroparesis (gastric retention) may be a cause of poor glycemic control in some diabetic patients. Exogenous insulin may begin to act before food leaves the stomach, leading to hypoglycemia. Because metoclopramide affects the transport of food into the intestines, thus influencing the absorption rate, adjustments to insulin dosage or administration timing may be necessary. For more complete data on metoclopramide interactions (out of 10), please visit the HSDB record page. Non-human toxicity values: Oral LD50 (rat): 750 mg/kg Intraperitoneal LD50 (rat): 114 mg/kg Subcutaneous LD50 (rat): 340 mg/kg Intravenous LD50 (rat): 50 mg/kg For more complete data on metoclopramide non-human toxicity values (out of 8), 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

Antiemetic; Dopamine Antagonist
Metoclopramide tablets are indicated for short-term (4 to 12 weeks) treatment of symptomatic, confirmed gastroesophageal reflux disease in adult patients who have not responded to conventional treatment. /US Product Label Includes/
Metoclopramide tablets (USP) are indicated for the relief of symptoms associated with acute and recurrent diabetic gastric retention. Common manifestations of delayed gastric emptying (such as nausea, vomiting, heartburn, persistent postprandial fullness, and anorexia) respond differently to metoclopramide tablets. Nausea symptoms are significantly relieved early and continue to improve within three weeks. Relief from vomiting and anorexia may occur a week or longer than relief from abdominal distension. /US Product Label Includes/
Metoclopramide injection is indicated for the prevention of emetic vomiting induced by chemotherapy in cancer. /US Product Label Includes/
For more complete data on the therapeutic uses of metoclopramide (8 types), please visit the HSDB record page.

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Drug Warning
Warning: Tardive dyskinesia—Metoclopramide treatment may cause tardive dyskinesia, a serious and usually irreversible movement disorder. The risk of developing tardive dyskinesia increases with the duration of treatment and the cumulative total dose. If a patient develops signs or symptoms of tardive dyskinesia, metoclopramide treatment should be discontinued. There is currently no known treatment for tardive dyskinesia. In some patients, symptoms may lessen or disappear after discontinuation of metoclopramide treatment.Except in very rare cases where the benefit of treatment is considered to outweigh the risks of tardive dyskinesia, metoclopramide treatment should be avoided for more than 12 weeks. Adverse reactions to metoclopramide typically involve the central nervous system and gastrointestinal tract, and are usually mild, transient, and reversible upon discontinuation. Generally, the incidence of adverse reactions to metoclopramide is dose- and duration-related. The most common adverse reaction to metoclopramide involves the central nervous system. Patients taking this medication have reported agitation, drowsiness, fatigue, and lethargy; these symptoms occur in approximately 10% of patients at a dose of 10 mg four times daily. Insomnia, headache, confusion, dizziness, or depression with suicidal ideation are less common. Higher doses increase the risk of drowsiness; approximately 70% of patients experience drowsiness at doses of 1–2 mg/kg. While a causal relationship between metoclopramide and seizures has not been established, rare seizures have been reported. Reports of hallucinations are also rare. Anxiety or agitation may also occur, especially after rapid intravenous administration of the drug. Patients receiving metoclopramide may experience extrapyramidal reactions (e.g., acute dystonia, akathisia), which are apparently mediated by blocking central dopaminergic receptors involved in motor function. While extrapyramidal reactions can occur in all age groups and at any dose, they are more common in pediatric patients and adults under 30 years of age, especially after intravenous administration of high doses of the drug (e.g., for the prevention of vomiting induced by cancer chemotherapy). Extrapyramidal reactions typically occur within 24–48 hours of starting treatment and usually subside within 24 hours of discontinuation. For more complete data on drug warnings for metoclopramide (31 in total), please visit the HSDB records page. Pharmacodynamics: Metoclopramide promotes gastric emptying by reducing lower esophageal sphincter (LES) pressure. It also acts on the posterior brain region to prevent and relieve nausea and vomiting. Furthermore, this drug increases gastrointestinal motility without increasing bile, gastric juice, or pancreatic juice secretion. Due to its anti-dopaminergic activity, metoclopramide can cause tardive dyskinesia (TD), dystonia, and akathisia; therefore, it should not be used continuously for more 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.)