Products
Lubiprostone is commercially available in the form of soft capsules (Amitiza). It has been approved in many countries since 2009.
Structure and properties
Lubiprostone (C20H32F2O5, Mr = 390.46) is a white, odorless powder that is insoluble in water and soluble in ethanol and ether. It is a derivative of a metabolite of prostaglandin E1. It is a bicyclic fatty acid of the prostone group and exists in two tautomers, only one of which is active.
Effects
Lubiprostone (ATC A06AX03) promotes regular bowel emptying and improves symptoms associated with constipation. Its efficacy has been studied in large clinical trials. It activates the voltage-gated ClC-2 chloride channel in the small and large intestines. The channels are localized to the apical cell membrane of mucosal epithelial cells and mediate the transport of chloride ions into the intestinal lumen. This results in a paracellular outflow of sodium and water, increasing secretion of fluid into the intestine (Figure 2, click to enlarge). Bowel motility increases, transit time is shortened, stool becomes softer, and the extra volume triggers the defecation reflex. Lubiprostone is selective and does not activate other chloride channels such as CFTR (cystic fibrosis transmembrane conductance regulator). Activation is independent of protein kinase A. Serum electrolyte levels of chloride, sodium, and potassium were also unaffected.
Indications
Lubiprostone is approved in many countries for the treatment of chronic idiopathic constipation (constipation) in adults 18 years of age and older. In the United States, in addition to the 24 μg capsules, 8 μg capsules are also commercially available for the treatment of IBS-C (Irritable Bowel Syndrome with Constipation) in women 18 years of age and older. Efficacy and safety in other indications and patient populations are being discussed and studied, including use in children, impaired liver function, and opioid-induced constipation.
Dosage
Capsules are taken whole with a meal and water in the morning and evening. Taking with food is recommended because it may reduce the development of nausea.
Contraindications
Lubiprostone is contraindicated in hypersensitivity and intestinal obstruction. Lubiprostone should not be taken during pregnancy or lactation, and a reliable method of contraception must be used in women of childbearing age. For complete precautions, see the drug label.
Interactions
Lubiprostone acts primarily locally in the intestine and is absorbed only in small amounts. It has a low bioavailability of < 1% and occurs in plasma at very low concentrations. It is rapidly biotransformed in the gastrointestinal tract by a carbonyl reductase to the major metabolite M3 and has a short half-life. According to in vitro studies, cytochromes P450 are not thought to be involved in metabolism. Lubiprostone is not an inhibitor or inducer of CYPs.
Adverse effects
The most commonly observed adverse effects include gastrointestinal disturbances such as nausea, vomiting, diarrhea, incontinence, abdominal cramps and pain, and flatulence. Nausea is common and dose-dependent. Taking with food may reduce the frequency of occurrence. Cases of dyspnea (difficulty breathing) with a tightness in the chest after the first dose have been reported. Electrolyte disturbances did not occur. Adverse effects are dose-dependent. The following adverse effects were further observed in clinical studies: Headache, syncope, temor, taste disturbances, paresthesias, rigor, pain, weakness, feeling sick, oedema, asthma, difficulty breathing, sweating, urticaria, rash, nervousness, flushing, palpitations, loss of appetite, dizziness.
