Ki: 3 nM (μ opioid receptor), 48 nM (δ opioid receptor), 1156 nM (κ opioid receptor)[1]

Absorption, Distribution and Excretion
Loperamide is well absorbed from the gastrointestinal tract; however, it undergoes extensive first-pass metabolism, forming metabolites excreted via bile. Therefore, very little loperamide actually enters systemic circulation. The bioavailability is less than 1%. After oral administration of 2 mg loperamide capsules, the plasma concentration of the unchanged drug is less than 2 ng/mL. Peak plasma concentrations of loperamide are reached approximately 5 hours after oral administration of capsules and approximately 2.5 hours after oral administration of liquid formulations. Loperamide and its metabolites in systemic circulation are excreted via bile. Undigested loperamide and its metabolites are primarily excreted via feces. Only 1% of the absorbed dose is excreted unchanged in the urine. Loperamide has a large volume of distribution. Despite its high lipophilicity, loperamide cannot cross the blood-brain barrier and typically exerts peripheral effects.
In this study, tritium-labeled loperamide was orally administered to eight groups (n=5 per group) of fasted male Wistar rats (250 ± 10 g) at a dose of 1.25 mg/kg. Urine and feces were collected over four days. Rats were sacrificed at different time points from 1 to 96 hours post-administration for examination of blood, organs, and tissues. One rat was cannulated into a bile duct for 48 hours. The radioactivity content of each sample was determined, and the contents of loperamide, metabolites, and volatile radioactive substances were determined using reverse isotope dilution and lyophilization methods. Only 5% of the drug and its metabolites were recovered from the urine, with the majority excreted in the feces. Plasma drug concentrations were low at all time points. The maximum plasma concentration of unmetabolized loperamide did not exceed 0.22% of the administered dose, equivalent to approximately 75 mg/mL plasma. One hour after administration, approximately 85% of the loperamide remained in the gastrointestinal tract. The drug concentration in brain tissue was extremely low, never exceeding 22 ng/g brain tissue, or 0.005% of the administered dose. Studies confirmed enterohepatic shunting, but the amount of drug entering systemic circulation was very low. Differentiation between total and non-volatile radioactivity indicated that most residual organ radioactivity originated from tritium-contaminated water. Three male volunteers were orally administered 2.0 mg of 3H-loperamide (specific activity 64 mCi/mM) in gelatin capsules. Control samples of blood, urine, and feces were collected before administration. Blood samples were collected at 1, 2, 4, 8, 24, 72, and 168 hours post-administration under heparin anticoagulation. Urine was collected for 7 consecutive days, and feces for 8 consecutive days. The radioactivity content of each sample was determined, and the levels of loperamide, metabolites, and volatile radioactive substances were determined using reverse isotope dilution and lyophilization methods. The metabolism of orally administered 3H-loperamide in humans was similar to that in rats. Peak plasma concentrations of loperamide occur 4 hours after administration, below 2 ng/mL, representing approximately 0.3% of the administered dose. Approximately 1% of the administered dose is excreted unchanged in the urine, and 6% is excreted as non-volatile metabolites. Approximately 40% of the administered dose is excreted in the feces, primarily within the first 4 days after administration; of this, 30% is the unchanged drug. Rat distribution studies indicate that loperamide has a high affinity for the intestinal wall and preferentially binds to receptors in the longitudinal muscle layer. The plasma protein binding rate of loperamide is 95%, primarily binding to albumin. Non-clinical data suggest that loperamide is a substrate of P-glycoprotein. /Breast Milk/ Human milk may contain trace amounts of loperamide. For more complete data on the absorption, distribution, and excretion of loperamides (8 types), please visit the HSDB record page.

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Metabolism/Metabolites
Loperamide is widely metabolized. The primary metabolic pathway is oxidative N-demethylation mediated by CYP2C8 and CYP3A4, yielding N-demethylloperamide. CYP2B6 and CYP2D6 play minor roles in the N-demethylation of loperamide. Loperamide metabolites have no pharmacological activity. Loperamide is almost entirely extracted by the liver, primarily metabolized and conjugated in the liver, and excreted via bile. Oxidative N-demethylation is the main metabolic pathway of loperamide, primarily mediated by CYP3A4 and CYP2C8. Due to its extremely high first-pass effect, plasma concentrations of unmetabolized drug are extremely low. Unlike the Parkinson's-like effects associated with the mitochondrial neurotoxin N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and the antipsychotic drug haloperidol, there are currently no reports of adverse central nervous system (CNS) reactions caused by structure-related N-substituted-4-arylpiperidin-4-ol derivatives and the antidiarrheal drug loperamide. While this difference may be attributed to the P-glycoprotein substrate properties of loperamide preventing its entry into the brain, another possibility is that the metabolism of loperamide in humans differs from that of MPTP and haloperidol, and does not involve bioactivation into neurotoxic pyridines. This study focused on the identification of pyridine metabolites and investigated the bioactivation process of loperamide. The loss of NADPH dependence of loperamide was observed in both rat and human liver microsomes (human liver microsomal half-life t_1/2 = 13 min; rat liver microsomal half-life t_1/2 = 22 min). The metabolic pathways of loperamide in humans and rats are similar, with the primary pathway being N-dealkylation to N-demethylloperamide (M3). Other biotransformation pathways of loperamide include N-hydroxylation and C-hydroxylation, yielding loperamide-N-oxide (M4) and carbinolamide (M2), respectively. Furthermore, the formation of another metabolite (M5) was detected in human and rat liver microsomes. The structure of M5 was determined to be a pyridinium ion (LPP⁺) by comparing the characteristics of LLC/tandem mass spectrometry with the pyridinium ion generated by the chemical reaction of loperamide. The metabolism of loperamide in human liver microsomes is sensitive to ketoconazole and bupropion treatment, suggesting the involvement of P4503A4 and P4502B6. Recombinant P4503A4 catalyzes all biotransformation pathways of loperamide in human liver microsomes, while P4502B6 is only responsible for N-dealkylation and N-oxidation pathways. Although loperamide is metabolized into a potentially neurotoxic pyridine, its safety profile remains relatively high (compared to MPTP and haloperidol), possibly due to the combined effect of several factors, including the typically short treatment duration of only a few days, and the fact that loperamide (and perhaps LPP(+)) is a substrate of a P-glycoprotein, thus preventing its entry into the central nervous system. Although haloperidol and loperamide share a common bioactivation process, their safety profiles differ, supporting the view that not all compounds that are bioactivated in vitro will cause toxicological reactions in vivo. Loperamide's known metabolites include N-desmethylpiperidine. The apparent elimination half-life of loperamide is 10.8 hours, ranging from 9.1 to 14.4 hours. In healthy adults, the apparent elimination half-life of loperamide is 10.8 hours (range 9.1–14.4 hours).

Toxicity Summary
Identification and Uses: Loperamide is a solid. Loperamide is used to control and relieve acute nonspecific diarrhea and symptoms of chronic diarrhea associated with inflammatory bowel disease. Human Exposure and Toxicity: Loperamide is an over-the-counter antidiarrheal medication with μ-opioid receptor agonist activity. Due to its low bioavailability and extremely poor central nervous system penetration, no central nervous system opioid effects have been observed after oral administration of therapeutic doses. However, central nervous system opioid effects have been observed after oral administration of supertherapeutic doses. There have been reports of oral loperamide abuse as an opioid substitute in patients attempting to self-treat opioid addiction. Ventricular arrhythmias, QRS duration prolongation, and QTc interval prolongation have been reported after oral loperamide abuse. Post-marketing experience indicates rare reports of paralytic ileus associated with abdominal distension. These cases mostly occurred in patients with acute dysentery, those who overdose, or children under 2 years of age. Animal Studies: Loperamide administration significantly inhibited foraging behavior and reduced body weight in rats. Intravenous administration of loperamide caused an immediate decrease in blood pressure and heart rate in anesthetized rats. A rat study using loperamide at doses up to 133 times the maximum human dose (calculated in mg/kg) for 18 months found no evidence of carcinogenicity. Beagles were administered loperamide gelatin capsules at doses of 5.0, 1.25, and 0.31 mg/kg, 6 days a week for 12 months. Some depressive symptoms were observed during the first week of administration at the 1.25 and 5 mg/kg doses. For the remainder of the experiment, all animals behaved and appeared normal, except for occasional bloody stools in the 5 mg/kg dose group and soft stools in the 0.31 and 1.25 mg/kg dose groups (especially during the first 6 weeks of administration). Primiparous female rats were supplemented with 40, 10, and 2.5 mg/100 g of loperamide, respectively, during days 6 to 15 of gestation. The fetuses were delivered by cesarean section on day 22 of gestation. In the 40 mg/100 g diet group, only 1 out of 20 female rats successfully became pregnant. There were no significant differences between the control group and the 2.5 mg/100 g and 10 mg/100 g diet groups in pregnancy rate, number of implantations per female, number of pups, percentage of live, stillborn, and resorbed fetuses, distribution of live, stillborn, and resorbed fetuses in the left and right horns of the uterus, or weight of live pups. No gross visceral or skeletal malformations were observed. In vivo and in vitro studies have shown that loperamide is not genotoxic.

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Hepatotoxicity
As with most currently used opioids, loperamide treatment was not associated with elevated serum enzymes. There are currently no conclusive case reports indicating that either drug causes specific acute, clinically significant liver injury. The lack of hepatotoxicity may be related to the low dose used and low systemic absorption. Absorbed loperamide is metabolized in the liver.
For references on the safety and potential hepatotoxicity of loperamide, please see the Opioids Overview section. Last updated: May 20, 2019
Drug Category: Gastrointestinal Drugs; Opioids
Pregnancy and Lactation Effects
◉ Overview of Lactation Use
Very small amounts of the loperamide prodrug enter breast milk. Use of standard doses of loperamide during lactation is unlikely to affect the infant.
◉ Effects on Breastfed Infants
No published information found as of the revision date.
◉ Effects on Lactation and Breast Milk
No published information found as of the revision date.
Protein Binding
According to literature, the plasma protein binding rate of loperamide is approximately 95%.
Drug Interactions
Non-clinical data indicate that loperamide is a substrate of P-glycoprotein. Concomitant use of loperamide (single dose 16 mg) with quinidine or ritonavir (both P-glycoprotein inhibitors) resulted in a 2- to 3-fold increase in loperamide plasma concentrations. The clinical significance of this pharmacokinetic interaction with P-glycoprotein inhibitors when loperamide is administered at the recommended dose is unclear. Concomitant use of loperamide with oral desmopressin resulted in a 3-fold increase in desmopressin plasma concentrations, likely due to slowed gastrointestinal motility. Loperamide is biotransformed in vitro by cytochrome P450 (CYP) 2C8 and 3A4 and is a substrate of P-glycoprotein efflux transporters. This study aimed to investigate the effects of CYP3A4 and the P-glycoprotein inhibitor itraconazole and the CYP2C8 inhibitor gemfibrozil on the pharmacokinetics of loperamide. In a randomized, crossover, four-phase study, 12 healthy volunteers received 100 mg itraconazole (initial dose 200 mg), 600 mg gemfibrozil, itraconazole combined with gemfibrozil, or placebo twice daily for five consecutive days. On day 3, they received a single dose of 4 mg loperamide. Plasma and urinary concentrations of loperamide and N-desmethylloperamide were measured within 72 and 48 hours, respectively. The potential effects of loperamide on the central nervous system were assessed using the digit substitution test and subjective somnolence test. Itraconazole increased the peak plasma concentration (Cmax) of loperamide by 2.9-fold (range: 1.2–5.0; p < 0.001), the area under the plasma loperamide concentration-time curve (AUC_0-∞) by 3.8-fold (1.4–6.6; p < 0.001), and prolonged the elimination half-life (t_1/2) of loperamide from 11.9 hours to 18.7 hours (p < 0.001). Gemfibrozil increased the Cmax of loperamide by 1.6-fold (0.9–3.2; p < 0.05), the AUC_0-∞ by 2.2-fold (1.0–3.7; p < 0.05), and prolonged the t_1/2 to 16.7 hours (p < 0.01). The combination of itraconazole and gemfibrozil increased the Cmax of loperamide by 4.2-fold (1.5-8.7; P < 0.001), the AUC(0-∞) by 12.6-fold (4.3-21.8; P < 0.001), and prolonged the t(1/2) of loperamide to 36.9 hours (p < 0.001). Itraconazole, gemfibrozil, and their combination increased the urinary excretion of loperamide by 3.0-fold, 1.4-fold, and 5.3-fold, respectively, within 48 hours (p < 0.05). Itraconazole, gemfibrozil, and their combination decreased the plasma AUC(0-72) ratio of N-desmethylloperamide to loperamide by 65%, 46%, and 88%, respectively (p < 0.001). No significant differences were observed in the digit substitution test or subjective somnolence between different stages. Itraconazole, gemfibrozil, and their combination can significantly increase the plasma concentration of loperamide. Although not observed in the psychomotor tests used, an increased risk of adverse reactions should be considered when loperamide is used in combination with itraconazole, gemfibrozil, and especially the two.

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Non-human toxicity values
Canine intravenous LD50: 2.8 mg/kg
Canine oral LD50: >40 mg/kg
Guinea pig oral LD50: 41.5 mg/kg
Juvenile female rat oral LD50: 261 mg/kg
For more complete non-human toxicity data (out of 10), please visit the HSDB record page.

[1]. Loperamide (ADL 2-1294), an opioid antihyperalgesic agent with peripheral selectivity. J Pharmacol Exp Ther. 1999 Apr;289(1):494-502.

Therapeutic Uses

Antidiarrheal Drugs
/Clinical Trials/ ClinicalTrials.gov is a registry and results database that lists human clinical studies funded by public and private institutions worldwide. The website is maintained by the National Library of Medicine (NLM) and the National Institutes of Health (NIH). Each record on ClinicalTrials.gov includes a summary of the study protocol, including: the disease or condition; the intervention (e.g., the medical product, behavior, or procedure being studied); the title, description, and design of the study; participation requirements (eligibility criteria); the location of the study; contact information for the study location; and links to relevant information from other health websites, such as the NLM's MedlinePlus (for providing patient health information) and PubMed (for providing citations and abstracts of academic articles in the medical field). Loperamide is listed in the database.
Loperamide is used to control and relieve acute nonspecific diarrhea and chronic diarrhea symptoms associated with inflammatory bowel disease. /US Product Label Includes/
This combination drug containing loperamide and simethicone is used to control and relieve symptoms of diarrhea and may also relieve bloating, abdominal distension, and bloating pain. /US Product Label Includes/
For more complete data on the therapeutic uses of loperamide (7 types), please visit the HSDB record page.

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Drug Warnings
Loperamide is generally well tolerated; however, abdominal pain, bloating or discomfort, constipation, drowsiness, dizziness, fatigue, dry mouth, nausea and vomiting, and upper abdominal pain may occur. Children may be more susceptible to the central nervous system adverse reactions of this drug than adults. Hypersensitivity reactions, including rash, have been reported. Adverse reactions of loperamide are difficult to distinguish from the symptoms of diarrhea syndrome, but gastrointestinal adverse reactions have been reported less frequently with loperamide than with diphenoxylate in combination with atropine. Post-marketing experience indicates that paralytic ileus associated with abdominal distension has been reported in rare cases. These cases mostly occurred in patients with acute dysentery, those who overdosed, or children under 2 years of age. The safety and efficacy of loperamide in children under 2 years of age have not been established. Due to the wide variability in response in this age group, loperamide should be used with extreme caution in young children. Dehydration, especially in young children, may further affect the variability in drug response. Loperamide should not be used to treat diarrhea or pseudomembranous colitis caused by certain infections (e.g., antibiotic-associated pseudomembranous colitis). Loperamide is contraindicated in patients with known hypersensitivity to loperamide and in patients who need to avoid constipation. Patients taking loperamide should consult a doctor if diarrhea persists for more than 2 days, symptoms worsen, abdominal distension or bloating develops, or fever occurs. Loperamide should not be used for more than 2 days without a doctor's instruction. It should not be used without a doctor's prescription. It should also not be used without a doctor's prescription if diarrhea is accompanied by high fever (above 38.3°C), bloody stools, or a history of rash or other drug allergic reactions. Patients taking anti-infective medications or with a history of liver disease should consult a doctor before self-medicating. For more complete data on drug warnings for loperamide (12 in total), please visit the HSDB records page.

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Pharmacodynamics
Loperamide is an antidiarrheal medication that relieves diarrhea symptoms. It reduces gastrointestinal motility and fluid secretion, slows colonic transit time, and increases the absorption of fluids and electrolytes in the gastrointestinal tract. Loperamide also enhances rectal tone, reduces daily stool volume, and increases stool viscosity and bulk density. It also enhances anal sphincter tone, thereby reducing incontinence and urgency. The onset of action is approximately 1 hour, and the effect can last up to 3 days. Although loperamide is a potent μ-opioid receptor agonist, its analgesic effect is not significant at therapeutic and supratherapeutic doses. However, high doses of loperamide can inhibit P-glycoprotein-mediated drug efflux, allowing it to cross the blood-brain barrier, thereby exerting central opioid effects and leading to toxicity. At extremely high plasma concentrations, loperamide can interfere with cardiac conduction. Because loperamide inhibits sodium-gated cardiac channels and potassium channels associated with ether-a-go-go genes, it can prolong the QRS complex and QTc interval, leading to ventricular arrhythmias, monomorphic and polymorphic ventricular tachycardia, torsades de pointes, ventricular fibrillation, Brugada syndrome, cardiac arrest, and death.

C29H33CLN2O2

477.04

476.223

53179-11-6

Loperamide-d6;1189574-93-3

3955

Typically exists as solid at room temperature

1.187g/cm3

647.2ºC at 760 mmHg

220-228

345.2ºC

1.6

5.025

1

3

7

34

623

0

CN(C)C(=O)C(CCN1CCC(CC1)(C2=CC=C(C=C2)Cl)O)(C3=CC=CC=C3)C4=CC=CC=C4

RDOIQAHITMMDAJ-UHFFFAOYSA-N

InChI=1S/C29H33ClN2O2/c1-31(2)27(33)29(24-9-5-3-6-10-24,25-11-7-4-8-12-25)19-22-32-20-17-28(34,18-21-32)23-13-15-26(30)16-14-23/h3-16,34H,17-22H2,1-2H3

4-[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]-N,N-dimethyl-2,2-diphenylbutanamide

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

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

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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