メトクロプラミド

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.

Serum aminotransferase elevations during metoclopramide therapy are uncommon and rates of such elevations were not reported in the large clinical trials demonstrating its efficacy in motility disorders. Metoclopramide has been listed as a cause of clinically apparent liver injury in several large series of drug induced liver disease, but without documentation of the nature of the injury or degree of causality assessment. Clinical descriptions of liver injury attributable to metoclopramide are few, but the latency to onset of liver injury is usually less than 30 days and the pattern of liver enzyme elevations cholestatic. Immunoallergic features are not prominent. Prolonged jaundice and persistent pruritus suggestive of bile duct loss and vanishing bile duct syndrome has been described. Metoclopramide has not been listed as a cause of acute liver failure in large clinical series.

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 120(SRC), determined from a log Kow of 2.62(2) and a regression-derived equation(3), indicates that metoclopramide is expected to have high mobility in soil(SRC). The pKa of metoclopramide is 9.27(4), indicating that this compound will partially exist in the cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(5). Volatilization from moist soil is not expected because the compound exists as a cation and cations do not volatilize. Metoclopramide is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 4.6X10-9 mm Hg at 25 °C(SRC), determined from a fragment constant method(6). Biodegradation data in soil were not available(SRC, 2010).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 120(SRC), determined from a log Kow of 2.62(2) and a regression-derived equation(3), indicates that metoclopramide is not expected to adsorb to suspended solids and sediment(SRC). A pKa of 9.27(4) indicates metoclopramide will exist partially in the cation form at pH values of 5 to 9 and therefore volatilization from water surfaces is not expected to be an important fate process(SRC). According to a classification scheme(5), an estimated BCF of 25(SRC), from its log Kow(2) and a regression-derived equation(2), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Biodegradation data in water were not available(SRC, 2010).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), metoclopramide, which has an estimated vapor pressure of 4.6X10-9 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase metoclopramide may be removed from the air by wet or dry deposition(SRC). Metoclopramide contains chromophores that absorb at wavelengths >290 nm(3), and therefore will be susceptible to direct photolysis by sunlight(SRC).

The Koc of metoclopramide is estimated as 120(SRC), using a log Kow of 2.62(1) and a regression-derived equation(2). According to a classification scheme(3), this estimated Koc value suggests that metoclopramide is expected to have high mobility in soil. The pKa of metoclopramide is 9.27(4), indicating that this compound will almost entirely exist in the cation form in the environment and cations generally do adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(5).

/HUMAN EXPOSURE STUDIES/ Metoclopramide, a central and peripheral dopamine type 2 receptor antagonist, has been used as an attractive and safer alternative to cisapride. However, cardiac side-effects have also been reported with this drug. To evaluate the effects of intravenous metoclopramide administration on cardiac repolarization using QT dynamicity, a reliable indicator of arrhythmic side-effects. The effect of metoclopramide on cardiac repolarization was evaluated in 10 healthy male volunteers in the supine position. Metoclopramide (10 mg) or placebo was administered intravenously at random in a double-blind, cross-over manner to the participants during continuous electrocardiographic recording in the supine position. The 30-min stationary segments of the recordings before and after drug administration were used to investigate QT dynamicity. Metoclopramide administration, but not placebo, resulted in steeper QT/RR slopes compared with the pre-drug values (metoclopramide: 0.037 +/- 0.004 vs. 0.064 +/- 0.012; P = 0.041; placebo: 0.045 +/- 0.006 vs. 0.050 +/- 0.004; P = 0.563). In a two-way analysis of variance model, metoclopramide administration also increased the QT variance independently (F = 6.225, P = 0.023). Metoclopramide administration increases the QT/RR slope and QT variance. ...

/HUMAN EXPOSURE STUDIES/ To investigate the effect of metoclopramide on breast milk volume and duration of breastfeeding in women delivering preterm. Women who planned to breastfeed and delivered between 23 and 34 weeks of gestation were eligible to participate in this randomized, double-blind, placebo-controlled study. Women were randomized to receive 10 mg of metoclopramide or placebo 3 times a day for 10 days, starting within 96 hours of birth. Breastfeeding education was standardized for all women. Mothers recorded the volume of breast milk expressed at each pumping for 17 days. Duration of breastfeeding was measured by monthly follow-up phone calls to each subject. Sixty-nine women were enrolled and 57 (82%) women completed the study: 28 in the metoclopramide group and 29 in the placebo group. The 2 groups were similar in age, education, ethnicity, gestational age, and marital status. There was no significant difference between breast milk volumes in the metoclopramide and placebo groups at each of the 17 days of the study (P = .26 to .98; test for mean metoclopramide effect P = .80). There was no significant difference between groups in duration of breastfeeding, with a median of 8.8 weeks, an interquartile range of 3.4 to 12.0 weeks for the metoclopramide group and a median of 8.6 weeks, and an interquartile range of 5.6 to 16.9 weeks for the placebo group (P = .09). Metoclopramide did not improve breast milk volume or duration of breastfeeding in this population of women. Regardless of therapy received, breastfeeding duration in this study of preterm mothers was poor.

/HUMAN EXPOSURE STUDIES/ The objective is to determine cardiovascular and insulin release effects under metoclopramide (MTC) and dopamine (DA) infusion by using an acute comparative design with the intravenous infusion of both drugs. /Investigators/ evaluated 15 normal (normotensive and normoglycemic) subjects, 13 hypertensive, and 15 type 2 diabetic subjects. Subjects were submitted to an experimental design in which we first gave them a 0.9% saline solution for 30 minutes, and then administered MTC at 7.5 ug kg min through an intravenous infusion during a period of 30 minutes. Although subjects were receiving MTC, /investigators/ added an intravenous infusion of DA at 1-3 ug kg min during 30 minutes. Blood pressure, heart rate, serum lipid profile, and insulin levels were measured. Sympathetic reactivity by the cold pressor test was also measured. In normotensive subjects, there was a systolic blood pressure and heart rate increase during MTC plus DA infusion. In subjects with diabetes mellitus there was a heart rate increase without changes in blood pressure during the MTC plus DA infusion period. In hypertensive subjects, MTC induced a significant decrease of systolic and diastolic blood pressure. During MTC plus DA period there was an increase of heart rate but no significant changes in blood pressure. During cold pressor test in both diabetic and hypertensive subjects, there were significant increases of both blood pressure and heart rate. Insulin serum levels increased in normotensive and hypertensive subjects but were attenuated in subjects with diabetes mellitus.

Drug-Induced Liver Injury Severity and Toxicity (DILIst)

metoclopramide

DILI Positive

Oral

DOI:10.1016/j.drudis.2019.09.022

An estimated BCF of 25 was calculated in fish for metoclopramide(SRC), using a log Kow of 2.62(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC).

A pKa of 9.27(1) indicates metoclopramide will exist almost entirely in the cation form at pH values of 5 to 9 and therefore volatilization from water and moist soil surfaces is not expected to be an important fate process(SRC). Metoclopramide is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 4.6X10-9 mm Hg(SRC), determined from a fragment constant method(2).

/BEHAVIORAL STUDIES/ Metoclopramide is an antidopaminergic drug that binds D2 receptor at the central nervous system and peripheral levels. Recent studies have demonstrated the presence of a sexually dimorphic nucleus in the anterior hypothalamus of rats and humans. The sexual differentiation of brain and its expression on sexual behavior is directed by catecholamines and steroids, which in turn will determine the masculinization of the preoptic area of the hypothalamus. Metoclopramide blocking dopaminergic receptor inhibits dopamine action and therefore brain masculinization. To determine the effects of the administration of this antidopaminergic drug in neonatal male rats, the design of the study considered measurements of mounts, penis intromission, and ejaculation in adult male rats treated neonatally with 100 ug metoclopramide. The administration of the drug or the vehicle (control) was by subcutaneous route during the third and fifth days of postnatal life. Six of 10 neonatally treated rats did not express male sexual activity in adulthood, while all control rats showed the characteristic pattern of male sexual behavior. Frequency of ejaculation in the rats treated with metoclopramide was 1.5 +/- 1 as compared to 5.0 +/- 0.9 in control rats (p < .01). There were meaningful differences with respect to the frequency of intromission in experimental rats (16 +/- 8) compared to control rats (115 +/- 18; p < .01). There is strong evidence that metoclopramide neonatally administered inhibits male sexual behavior in adult rats. Dopamine may be implicated in the process of neonatal brain sexual differentiation.

/GENOTOXICITY/ Metoclopramide (MCA) and procainamide (PCA), two widely used benzamide drugs developed before the present regulatory climate but recently found to induce DNA breaks in human lymphocytes, were evaluated for their genotoxic effects in cultured rodent and human cells. In subtoxic concentrations neither MCA (from 0.10 to 0.32 mM) nor PCA (from 0.18 to 0.56 mM) induced DNA fragmentation and repair in primary cultures of metabolically competent rat and human hepatocytes. In the absence of metabolic activation a meaningful increase in the frequency of 6-thioguanine-resistant V79 cells was produced by the maximum tolerated concentration of MCA (3.2 mM), whereas PCA resulted nonmutagenic. Any clastogenic effect was absent in human lymphocytes exposed to MCA for 28 hr, but a statistically significant increase in the frequency of micronucleated cells was observed when the exposure was prolonged to 72 hr. ...

/GENOTOXICITY/ The DNA-damaging and clastogenic activities of metoclopramide (MCA) and procainamide (PCA), two substituted benzamides not systematically tested for genotoxicity before clinical use, were investigated in rats given a single high oral dose (500 mg/kg) of these drugs. Neither MCA nor PCA induced DNA fragmentation in liver, kidney, gastric mucosa, spleen, and bone marrow, as detected by the alkaline elution technique. Moreover, neither drug increased the frequency of micronucleated hepatocytes and the frequency of micronucleated polychromatic erythrocytes in the bone marrow of partially hepatectomized rats. ...

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, including metoclopramide hydrochloride, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Metoclopramide hydrochloride/

MEDICATION

MEDICATION (VET)

Use (kg) in Switzerland (2009): >75