Eluxadoline, sold under the brand names Viberzi and Truberzi, is a medication taken

by mouth Oral administration is a route of administration whereby a substance is taken through the Human mouth, mouth, swallowed, and then processed via the digestive system. This is a common route of administration for many medications. Oral administ ...

for the treatment of

diarrhea Diarrhea (American English), also spelled diarrhoea or diarrhœa (British English), is the condition of having at least three loose, liquid, or watery bowel movements in a day. It often lasts for a few days and can result in dehydration d ...

and

abdominal pain Abdominal pain, also known as a stomach ache, is a symptom associated with both non-serious and serious medical issues. Since the abdomen contains most of the body's vital organs, it can be an indicator of a wide variety of diseases. Given th ...

in individuals with diarrhea-predominant

irritable bowel syndrome Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder characterized by a group of symptoms that commonly include abdominal pain, abdominal bloating, and changes in the consistency of bowel movements. These symptoms may ...

(IBS-D). It was approved for use in the United States in 2015. The

drug A drug is any chemical substance other than a nutrient or an essential dietary ingredient, which, when administered to a living organism, produces a biological effect. Consumption of drugs can be via insufflation (medicine), inhalation, drug i ...

originated from

Janssen Pharmaceutica Johnson & Johnson Innovative Medicine (formerly Janssen Pharmaceuticals) is a Belgian pharmaceutical company headquartered in Beerse, Belgium, and wholly owned by Johnson & Johnson. It was founded in 1953 by Paul Janssen. In 1961, Janssen Ph ...

and was developed by

Actavis Actavis Generics (formerly known as Watson Pharmaceuticals and Actavis plc, prior to the acquisition of Irish-based Allergan, Inc.) is a global pharmaceutical company focused on acquiring, developing, manufacturing and marketing branded pharmaceut ...

Contraindications

This drug is contraindicated in case of having: * Blockage of the

gallbladder In vertebrates, the gallbladder, also known as the cholecyst, is a small hollow Organ (anatomy), organ where bile is stored and concentrated before it is released into the small intestine. In humans, the pear-shaped gallbladder lies beneath t ...

or a

sphincter of Oddi The sphincter of Oddi (SO) (also hepatopancreatic sphincter or Glisson's sphincter), is a sphincter, a muscular valve that, in humans and some animals, controls the flow of bile and pancreatic juice out of the gallbladder and pancreas respective ...

problem * Problems with excessive alcohol use *

Pancreatitis Pancreatitis is a condition characterized by inflammation of the pancreas. The pancreas is a large organ behind the stomach that produces digestive enzymes and a number of hormone A hormone (from the Ancient Greek, Greek participle , "se ...

* Liver problems * Chronic or severe

constipation Constipation is a bowel dysfunction that makes bowel movements infrequent or hard to pass. The Human feces, stool is often hard and dry. Other symptoms may include abdominal pain, bloating, and feeling as if one has not completely passed the ...

Adverse effects

Common adverse effects are constipation and nausea, but rates of discontinuation due to constipation were low for both eluxadoline and

placebo A placebo ( ) can be roughly defined as a sham medical treatment. Common placebos include inert tablets (like sugar pills), inert injections (like saline), sham surgery, and other procedures. Placebos are used in randomized clinical trials ...

. Rare adverse effects:

fatigue Fatigue is a state of tiredness (which is not sleepiness), exhaustion or loss of energy. It is a signs and symptoms, symptom of any of various diseases; it is not a disease in itself. Fatigue (in the medical sense) is sometimes associated wit ...

bronchitis Bronchitis is inflammation of the bronchi (large and medium-sized airways) in the lungs that causes coughing. Bronchitis usually begins as an infection in the nose, ears, throat, or sinuses. The infection then makes its way down to the bronchi. ...

, viral gastroenteritis. Rare serious adverse effects include

pancreatitis Pancreatitis is a condition characterized by inflammation of the pancreas. The pancreas is a large organ behind the stomach that produces digestive enzymes and a number of hormone A hormone (from the Ancient Greek, Greek participle , "se ...

with a general incidence of 0.3%: higher incidence with 100 mg dose (0.3%) than with 75 mg dose (0.2%). The risk is even greater in those who do not have a

and the medication is not recommended in this group. In March 2017, the U.S. Food and Drug Administration issued a safety alert for eluxadoline concerning an increased risk of serious pancreatitis in patients without a gallbladder. An FDA review found that in such patients, spasm of the

may lead to severe pancreatitis. The FDA reported that in some cases symptoms have occurred with just one or two doses at the recommended dosage for patients without a gallbladder (75 mg). Of two deaths associated with eluxadoline reported up to February 2017, both occurred in patients without a gallbladder.

Interactions

Elevated concentrations of eluxadoline were observed with co-administration of inhibitors of the transporter protein OATP1B1, such as

ciclosporin Ciclosporin, also spelled cyclosporine and cyclosporin, is a calcineurin inhibitor, used as an immunosuppressant medication. It is taken Oral administration, orally or intravenously for rheumatoid arthritis, psoriasis, Crohn's disease, nephr ...

, gemfibrozil, certain

antiretroviral The management of HIV/AIDS normally includes the use of multiple antiretroviral drugs as a strategy to control HIV infection. There are several classes of antiretroviral agents that act on different stages of the HIV life-cycle. The use of mu ...

rifampicin Rifampicin, also known as rifampin, is an ansamycin antibiotic used to treat several types of bacterial infections, including tuberculosis (TB), ''Mycobacterium avium'' complex, leprosy, and Legionnaires' disease. It is almost always used tog ...

, and eltrombopag. Concurrent use of other drugs that cause constipation, such as

opioids Opioids are a class of Drug, drugs that derive from, or mimic, natural substances found in the Papaver somniferum, opium poppy plant. Opioids work on opioid receptors in the brain and other organs to produce a variety of morphine-like effects, ...

alosetron Alosetron, sold under the brand name Lotronex among others, is a 5-HT3 antagonist used for the management of severe diarrhea-predominant irritable bowel syndrome (IBS) in females only. It was patented in 1987 and approved for medical use in 20 ...

anticholinergic Anticholinergics (anticholinergic agents) are substances that block the action of the acetylcholine (ACh) neurotransmitter at synapses in the central nervous system, central and peripheral nervous system. These agents inhibit the parasympatheti ...

s, and

bismuth subsalicylate Bismuth subsalicylate, sold generically as pink bismuth and under brand names including Pepto-Bismol, Pepti-Calm, and BisBacter, is a medication used to treat temporary discomfort of the stomach and gastrointestinal tract. This includes an upset ...

, is not preferred. Eluxadoline increases the concentrations of drugs which are OATP1B1 and BCRP substrates. Co-administration of eluxadoline with

rosuvastatin Rosuvastatin, sold under the brand name Crestor among others, is a statin medication, used to prevent cardiovascular disease in those at high risk and treat dyslipidemia, abnormal lipids. It is recommended to be used with dietary changes, exer ...

may increase the risk of

rhabdomyolysis Rhabdomyolysis (shortened as rhabdo) is a condition in which damaged skeletal muscle breaks down rapidly. Symptoms may include muscle pains, weakness, vomiting, and confusion. There may be tea-colored urine or an irregular heartbeat. Some o ...

Pharmacology

Mechanism of action

Eluxadoline is a μ- and

κ-opioid receptor The κ-opioid receptor or kappa opioid receptor, abbreviated KOR or KOP for its ligand ketazocine, is a G protein-coupled receptor that in humans is encoded by the ''OPRK1'' gene. The KOR is coupled to the G protein Gi/G0 and is one of four re ...

agonist An agonist is a chemical that activates a Receptor (biochemistry), receptor to produce a biological response. Receptors are Cell (biology), cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an R ...

and

δ-opioid receptor The δ-opioid receptor, also known as delta opioid receptor or simply delta receptor, abbreviated DOR or DOP, is an inhibitory 7-transmembrane G-protein coupled receptor coupled to the G protein Gi alpha subunit, Gi/G0 and has enkephalins as it ...

antagonist An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain.enteric nervous system The enteric nervous system (ENS) is one of the three divisions of the autonomic nervous system (ANS), the others being the sympathetic nervous system (SNS) and parasympathetic nervous system (PSNS). It consists of a mesh-like system of neurons th ...

, possibly decreasing adverse effects on the

central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain, spinal cord and retina. The CNS is so named because the brain integrates the received information and coordinates and influences the activity o ...

Pharmacokinetics

In the ''in vitro'' studies, eluxadoline was found to be transported by OAT3 ( SLC22A8), OATP1B1 (

SLCO1B1 Solute carrier organic anion transporter family member 1B1 is a protein that in humans is encoded by the ''SLCO1B1'' gene. Pharmacogenomic research indicates that genetic variations in this gene are associated with response to simvastatin. Clini ...

), and BSEP ( ABCB11) at the highest concentrations tested (400 ng/ml, which is 162-fold larger than the observed C_max of the highest therapeutic dose of 100 mg). However, it was ''not'' to be transported by OCT1 POU2F1, OAT1 ( organic anion transporter 1), OCT2, OATP1B3 (

SLCO1B3 Solute carrier organic anion transporter family member 1B3 (SLCO1B3) also known as organic anion-transporting polypeptide 1B3 (OATP1B3) is a protein that in humans is encoded by the ''SLCO1B3'' gene. OATP1B3 is a 12-transmembrane domain influx tr ...

), P-gp (

P-glycoprotein P-glycoprotein 1 (permeability glycoprotein, abbreviated as P-gp or Pgp) also known as multidrug resistance protein 1 (MDR1) or ATP-binding cassette sub-family B member 1 (ABCB1) or cluster of differentiation 243 (CD243) is an important protein ...

), or BCRP ( ABCG2).

Multidrug resistance-associated protein 2 Multidrug resistance-associated protein 2 (MRP2) also called canalicular multispecific organic anion transporter 1 (cMOAT) or ATP-binding cassette sub-family C member 2 (ABCC2) is a protein that in humans is encoded by the ''ABCC2'' gene. Funct ...

(MRP2)-vesicular accumulation of eluxadoline was observed, indicating that the drug is a substrate of MRP2. Eluxadoline was not found to inhibit BCRP-, BSEP-, MRP2-, OCT1-, OCT2-, OAT1-, OAT3-, or OATP1B3-mediated transport of probe substrates but inhibited the transport of probe substrates of OATP1B1 and P-gp. In the ''in vitro'' studies, it was observed that eluxadoline is an ''in vivo'' substrate of OATP1B1, OAT3, and MRP2. Finally, no inhibition or induction of

cytochrome P450 Cytochromes P450 (P450s or CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that mostly, but not exclusively, function as monooxygenases. However, they are not omnipresent; for examp ...

enzymes was observed. Following a 100 mg dose of eluxadoline, the C_max was about 2 to 4 ng/ml and AUC was 12 to 22 ng.h/ml. Eluxadoline has linear

pharmacokinetics Pharmacokinetics (from Ancient Greek ''pharmakon'' "drug" and ''kinetikos'' "moving, putting in motion"; see chemical kinetics), sometimes abbreviated as PK, is a branch of pharmacology dedicated to describing how the body affects a specific su ...

with no accumulation upon repeated twice daily dosing. Taking eluxadoline with high fat meal decreased the C_max by 50% and AUC by 60%.

Chemistry

Synthesis

The synthesis of eluxadoline was published in 2006.
Process of the Preparation of Opioid modulators.

References

{{Irritable bowel syndrome Amines Antidiarrhoeals Carbamates Delta-opioid receptor antagonists Diarrhea Imidazoles Drugs developed by AbbVie Janssen Pharmaceutica Kappa-opioid receptor agonists Mu-opioid receptor agonists Peripherally selective drugs