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 to form metabolites that are excreted in the bile. Therefore, little loperamide actually reaches the systemic circulation. The drug bioavailability is less than 1%. Following oral administration of a 2 mg capsule of loperamide, plasma concentrations of unchanged drug were below 2 ng/mL. Plasma loperamide concentrations are highest approximately five hours after administration of an oral capsule of loperamide and 2.5 hours after the liquid formulation of the drug.
Loperamide and its metabolites in the systemic circulation undergo biliary excretion. Excretion of the unchanged loperamide and its metabolites mainly occurs through the feces. Only 1% of an absorbed dose excreted unchanged in the urine.
Loperamide has a large volume of distribution. Although highly lipophilic, loperamide does not cross the blood-brain barrier and generally acts peripherally.
Tritium-labelled loperamide was administered orally to eight groups of five fasted male Wistar rats (250 +/- 10 g) at a dosage of 1.25 mg/kg. Urine and feces were collected for up to 4 days. The rats were killed at different times from 1 to 96 hours after drug administration in order to examine blood, organs and tissues. In one rat, the bile was cannulated for 48 hours. The radioactive content of each sample was measured and the fractions due to loperamide, metabolites, and volatile radioactivity were determined by the inverse isotope dilution technique and lyophilization. Only 5% of the drug and its metabolites was recovered from the urine, the bulk being excreted with the feces. Drug plasma levels were low at all times. Maximum plasma levels of unchanged loperamide did not exceed 0.22% of the administered dose corresponding to about 75 mg/mL of plasma. The gastrointestinal tract contained about 85% of loperamide 1 hour after dosing. Brain levels were extremely low, never exceeding 22 ng/g brain tissue, or 0.005% of the administered dose. The existence of an enterohepatic shunt was shown, but the uptake of the drug into the general circulation was low. Differentiation between total radioactivity and nonvolatile radioactivity demonstrated that most of the residual organ radioactivity was due to tritiated water.
Three male volunteers received orally 2.0 mg of 3H-loperamide (specific activity 64 mCi/mM) in gelatine capsules. Control samples of blood, urine and feces were obtained before administration. Blood was collected on heparin 1, 2, 4, 8, 24, 72 and 168 hours thereafter. Urine was collected for seven days and feces for eight days. The radioactive content of each sample was measured and the fractions due to loperamide, metabolites and volatile radioactivity were determined by the inverse isotope dilution technique and lyophilization. The fate of orally administered 3H-loperamide in man appeared to be similar to that in rats. The peak plasma level of loperamide occurred 4 hours after treatment and was less than 2 ng/mL or about 0.3% of the administered dose. About 1% of the administered dose was excreted unaltered with the urine and 6% as nonvolatile metabolites. About 40% of the administered dose was excreted with the feces, mainly within the first four days; 30% of this amount was due to unchanged drug.
Studies on distribution in rats show a high affinity for the gut wall with a preference for binding to receptors of the longitudinal muscle layer. The plasma protein binding of loperamide is 95%, mainly to albumin. Non-clinical data have shown that loperamide is a P-glycoprotein substrate.
/MILK/ Small amounts of loperamide may appear in human breast milk.
For more Absorption, Distribution and Excretion (Complete) data for Loperamide (8 total), please visit the HSDB record page.

---

Metabolism / Metabolites
Loperamide is extensively metabolized. The primary metabolic pathway is oxidative N-demethylation mediated by CYP2C8 and CYP3A4, to form N-demethyl loperamide. CYP2B6 and CYP2D6 play a minor role in loperamide N-demethylation. Metabolites of loperamide are pharmacologically inactive.
Loperamide is almost completely extracted by the liver, where it is predominantly metabolized, conjugated and excreted via the bile. Oxidative N-demethylation is the main metabolic pathway for loperamide, and is mediated mainly through CYP3A4 and CYP2C8. Due to this very high first pass effect, plasma concentrations of unchanged drug remain extremely low.
In contrast with the Parkinson's-like effects associated with the mitochondrial neurotoxin N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and the neuroleptic agent haloperidol, there exist no reports on adverse central nervous system (CNS) effects with the structurally related N-substituted-4-arylpiperidin-4-ol derivative and antidiarrheal agent loperamide. Although this difference can be attributed to loperamide's P-glycoprotein substrate properties that prevent it from accessing the brain, an alternative possibility is that loperamide metabolism in humans is different from that of MPTP and haloperidol and does not involve bioactivation to a neurotoxic pyridinium species. In the current study, loperamide bioactivation was examined with particular focus on identification of pyridinium metabolites. A NADPH-dependent disappearance of loperamide was observed in both rat and human liver microsomes (human t(1/2) = 13 min; rat t(1/2) = 22 min). Loperamide metabolism was similar in human and rat and involved N-dealkylation to N-desmethylloperamide (M3) as the principal metabolic fate. Other routes of loperamide biotransformation included N- and C-hydroxylation to the loperamide-N-oxide (M4) and carbinolamide (M2) metabolites, respectively. Furthermore, the formation of an additional metabolite (M5) was also discernible in human and rat liver microsomes. The structure of M5 was assigned to the pyridinium species (LPP(+)) based on comparison of the liquid chromatography/tandem mass spectrometry characteristics to the pyridinium obtained from loperamide via a chemical reaction. Loperamide metabolism in human microsomes was sensitive to ketoconazole and bupropion treatment, suggesting P4503A4 and -2B6 involvement. Recombinant P4503A4 catalyzed all of the loperamide biotransformation pathways in human liver microsomes, whereas P4502B6 was only responsible for N-dealkylation and N-oxidation routes. The wide safety margin of loperamide (compared with MPTP and haloperidol) despite metabolism to a potentially neurotoxic pyridinium species likely stems from a combination of factors that include a therapeutic regimen normally restricted to a few days and the fact that loperamide and perhaps LPP(+) are P-glycoprotein substrates and are denied entry into the CNS. The differences in safety profile of haloperidol and loperamide despite a common bioactivation event supports the notion that not all compounds undergoing bioactivation in vitro will necessarily elicit a toxicological response in vivo.
Loperamide has known human metabolites that include N-Desmethyloperamide.

---

Biological Half-Life
The apparent elimination half-life of loperamide is 10.8 hours with a range of 9.1 to 14.4 hours.
The apparent elimination half-life of loperamide in healthy adults is 10.8 hours (range 9.1-14.4 hours).

Toxicity Summary
IDENTIFICATION AND USE: Loperamide is a solid. Loperamide is used in the control and symptomatic relief of acute nonspecific diarrhea and of chronic diarrhea associated with inflammatory bowel disease. HUMAN EXPOSURE AND TOXICITY: Loperamide is an over-the-counter antidiarrheal with mu-opioid agonist activity. Central nervous system opioid effects are not observed after therapeutic oral dosing because of poor bioavailability and minimal central nervous system penetration. However, central nervous system opioid effects do occur after supratherapeutic oral doses. Oral loperamide abuse as an opioid substitute has been seen among patients attempting to self-treat their opioid addiction. Ventricular dysrhythmias and prolongation of the QRS duration and QTc interval have been reported after oral loperamide abuse. In postmarketing experiences, paralytic ileus associated with abdominal distention has been reported rarely. Most of these cases occurred in patients with acute dysentery, following overdosage of the drug, or in children younger than 2 years of age. ANIMAL STUDIES: Loperamide administration significantly suppressed foraging behavior in rats and reduced their body weight. The intravenous injection of loperamide induced an immediate fall in blood pressure and heart rate in anesthetized rats. In a study in rats using loperamide dosages up to 133 times the maximum human dosage (on a mg/kg basis) for 18 months, there was no evidence of carcinogenicity. Beagle dogs were given loperamide in gelatin capsules at 5.0, 1.25 and 0.31 mg/kg six days a week for 12 months. Some depression was seen during the first week of drug administration at 1.25 and 5 mg/kg. Behavior and appearance were normal during the rest of the experiment, except that hemorrhagic stools were seen from time to time at 5 mg/kg and soft stools at 0.31 and 1.25 mg/kg, especially during the first 6 weeks of drug administration. Pregnant primiparous female rats were given loperamide in their diet at 40, 10 and 2.5 mg/100 g of food from day 6 through day 15 of pregnancy. On day 22, fetuses were delivered by caesarean section. At 40 mg/100 g food, only 1 female out of 20 became pregnant. There was no significant difference between the control group and the 2.5 and 10 mg/100 g food-dosed groups in pregnancy rate; number of implantations per dam; litter size, percentage of live, dead and resorbed fetuses; distribution of live, dead and resorbed fetuses in the left and right uterine horns; and body weight of live young. No macroscopic, visceral, or skeletal malformations were seen. Results of in vivo and in vitro studies carried out indicated that loperamide is not genotoxic.

---

Hepatotoxicity
As with most opiates in current use, therapy with loperamide has not been linked to serum enzyme elevations. There have been no convincing cases of idiosyncratic acute, clinically apparent liver injury attributed to either agent. The reason for its lack of hepatotoxicity may relate to the low doses used and lack of significant systemic absorption. What loperamide is absorbed is metabolized in the liver.
References on the safety and potential hepatotoxicity of loperamide are given in the overview section of the Opioids. Last updated: 20 May 2019
Drug Class: Gastrointestinal Agents; Opioids

---

Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
The amount of loperamide that enters milk from a prodrug of loperamide is minimal. Use of loperamide during breastfeeding is unlikely to affect the infant with standard doses.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

---

Protein Binding
Based on literature information, the plasma protein binding of loperamide is about 95%.

---

Interactions
Non-clinical data have shown that loperamide is a P-glycoprotein substrate. Concomitant administration of loperamide (16 mg single dose) with quinidine, or ritonavir, which are both Pglycoprotein inhibitors, resulted in a 2 to 3-fold increase in loperamide plasma levels. The clinical relevance of this pharmacokinetic interaction with P-glycoprotein inhibitors, when loperamide is given at recommended dosages is unknown.
Concomitant treatment /of loperamide/ with oral desmopressin resulted in a 3-fold increase of desmopressin plasma concentrations, presumably due to slower gastrointestinal motility.
Loperamide is biotransformed in vitro by the cytochromes P450 (CYP) 2C8 and 3A4 and is a substrate of the P-glycoprotein efflux transporter. Our aim was to investigate the effects of itraconazole, an inhibitor of CYP3A4 and P-glycoprotein, and gemfibrozil, an inhibitor of CYP2C8, on the pharmacokinetics of loperamide. In a randomized crossover study with 4 phases, 12 healthy volunteers took 100 mg itraconazole (first dose 200 mg), 600 mg gemfibrozil, both itraconazole and gemfibrozil, or placebo, twice daily for 5 days. On day 3, they ingested a single 4-mg dose of loperamide. Loperamide and N-desmethylloperamide concentrations in plasma were measured for up to 72 hr and in urine for up to 48 hr. Possible central nervous system effects of loperamide were assessed by the Digit Symbol Substitution Test and by subjective drowsiness. Itraconazole raised the peak plasma loperamide concentration (Cmax) 2.9-fold (range, 1.2-5.0; p < 0.001) and the total area under the plasma loperamide concentration-time curve (AUC(0-infinity)) 3.8-fold (1.4-6.6; p < 0.001) and prolonged the elimination half-life (t(1/2)) of loperamide from 11.9 to 18.7 hr (p < 0.001). Gemfibrozil raised the Cmax of loperamide 1.6-fold (0.9-3.2; P < 0.05) and its AUC(0-infinity) 2.2-fold (1.0-3.7; P < 0.05) and prolonged its t(1/2) to 16.7 hr (P < 0.01). The combination of itraconazole and gemfibrozil raised the Cmax of loperamide 4.2-fold (1.5-8.7; P < 0.001) and its AUC(0-infinity) 12.6-fold (4.3-21.8; P < 0.001) and prolonged the t(1/2) of loperamide to 36.9 hr (p < 0.001). The amount of loperamide excreted into urine within 48 hr was increased 3.0-fold, 1.4-fold and 5.3-fold by itraconazole, gemfibrozil and their combination, respectively (p < 0.05). Itraconazole, gemfibrozil and their combination reduced the plasma AUC(0-72) ratio of N-desmethylloperamide to loperamide by 65%, 46% and 88%, respectively (p < 0.001). No significant differences were seen in the Digit Symbol Substitution Test or subjective drowsiness between the phases. Itraconazole, gemfibrozil and their combination markedly raise the plasma concentrations of loperamide. Although not seen in the psychomotor tests used, an increased risk of adverse effects should be considered during concomitant use of loperamide with itraconazole, gemfibrozil and especially their combination.

---

Non-Human Toxicity Values
LD50 Dog iv 2.8 mg/kg
LD50 Dog oral >40 mg/kg
LD50 Guinea pig oral 41.5 mg/kg
LD50 Rat (young, female) oral 261 mg/kg
For more Non-Human Toxicity Values (Complete) data for Loperamide (10 total), 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
Antidiarrheals
/CLINICAL TRIALS/ ClinicalTrials.gov is a registry and results database of publicly and privately supported clinical studies of human participants conducted around the world. The Web site is maintained by the National Library of Medicine (NLM) and the National Institutes of Health (NIH). Each ClinicalTrials.gov record presents summary information about a study protocol and includes the following: Disease or condition; Intervention (for example, the medical product, behavior, or procedure being studied); Title, description, and design of the study; Requirements for participation (eligibility criteria); Locations where the study is being conducted; Contact information for the study locations; and Links to relevant information on other health Web sites, such as NLM's MedlinePlus for patient health information and PubMed for citations and abstracts for scholarly articles in the field of medicine. Loperamide is included in the database.
Loperamide is used in the control and symptomatic relief of acute nonspecific diarrhea and of chronic diarrhea associated with inflammatory bowel disease. /Included in US product label/
The fixed combination containing loperamide and simethicone is used for the control and symptomatic relief of diarrhea when relief of flatulence, bloating, and gas pain also is indicated. /Included in US product label/
For more Therapeutic Uses (Complete) data for Loperamide (7 total), please visit the HSDB record page.

---

Drug Warnings
Loperamide is generally well tolerated; however, abdominal pain, distention or discomfort, constipation, drowsiness, dizziness, fatigue, dry mouth, nausea and vomiting, and epigastric pain may occur. Children may be more sensitive to adverse CNS effects of the drug than adults. Hypersensitivity reactions including rash have been reported. Adverse effects of loperamide are difficult to distinguish from symptoms associated with the diarrheal syndrome, but adverse GI effects are reported to be less frequent after administration of loperamide than after administration of diphenoxylate with atropine. In postmarketing experiences, paralytic ileus associated with abdominal distention has been reported rarely. Most of these cases occurred in patients with acute dysentery, following overdosage of the drug, or in children younger than 2 years of age.
Safety and efficacy of loperamide in children younger than 2 years of age have not been established. Loperamide should be used with particular caution in young children because of the greater variability of response in this age group. The presence of dehydration, especially in younger children, may further influence the variability of response to the drug.
Loperamide should not be used in the treatment of diarrhea resulting from some infections or in patients with pseudomembranous colitis (e.g., associated with antibiotics). Loperamide is contraindicated in patients with a known hypersensitivity to the drug and in patients in whom constipation must be avoided.
Patients receiving loperamide should be advised to consult their clinician if the diarrhea persists for longer than 2 days, if symptoms worsen, if abdominal swelling or bulging develops, or if fever develops. For self-medication, loperamide should not be used for longer than 2 days unless directed by a clinician. Loperamide should also not be used for self-medication if diarrhea is accompanied by high fever (greater than 38.3 °C), if blood is present in the stool, or if rash or other allergic reaction to the drug has occurred previously. If a patient is receiving an anti-infective or has a history of liver disease, a physician should be consulted before the drug is used for self-medication.
For more Drug Warnings (Complete) data for Loperamide (12 total), please visit the HSDB record page.

---

Pharmacodynamics
Loperamide is an anti-diarrheal agent that provides symptomatic relief of diarrhea. It decreases peristalsis and fluid secretion in the gastrointestinal tract, delays colonic transit time, and increases the absorption of fluids and electrolytes from the gastrointestinal tract. Loperamide also increases rectal tone, reduces daily fecal volume, and increases the viscosity and bulk density of feces. It also increases the tone of the anal sphincter, thereby reducing incontinence and urgency. The onset of action is about one hour and the duration of action can be up to three days. While loperamide is a potent mu-opioid receptor agonist, it does not mediate significant analgesic activity at therapeutic and supratherapeutic doses. However, at high doses of loperamide, inhibition of P-glycoprotein-mediated drug efflux may allow loperamide to cross the blood-brain barrier, where loperamide can exert central opioid effects and toxicity. At very high plasma concentrations, loperamide can interfere with cardiac conduction. Because loperamide inhibits the Na⁺-gated cardiac channels and ether-a-go-go–related gene potassium channels, the drug can prolong the QRS complex and the QTc interval, which can lead to ventricular dysrhythmias, monomorphic and polymorphic ventricular tachycardia, torsade 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.

---

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).

View More

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)

---

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).

View More

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

---

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.

---

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