The metabolism of linaclotide was investigated in a set of experiments, predominantly in rodents. Linaclotide is metabolised in the intestine by immediate break down of the disulfide bridges which prone linaclotide to further digestion by the enzymes present in the gastrointestinal environment. Several breakdown products containing 3-13 amino acids have been identified. Only one metabolite, MM-419447, was shown to be pharmacodynamic active.
Linaclotide is metabolized within the gastrointestinal tract to its principal, active metabolite by loss of the terminal tyrosine moiety. Both linaclotide and the metabolite are proteolytically degraded within the intestinal lumen to smaller peptides and naturally occurring amino acids.
... We examined the metabolic stability of linaclotide in conditions that mimic the gastrointestinal tract and characterized the metabolite MM-419447 (CCEYCCNPACTGC), which contributes to the pharmacologic effects of linaclotide. Systemic exposure to these active peptides is low in rats and humans, and the low systemic and portal vein concentrations of linaclotide and MM-419447 observed in the rat confirmed both peptides are minimally absorbed after oral administration. Linaclotide is stable in the acidic environment of the stomach and is converted to MM-419447 in the small intestine. The disulfide bonds of both peptides are reduced in the small intestine, where they are subsequently proteolyzed and degraded. After oral administration of linaclotide, <1% of the dose was excreted as active peptide in rat feces and a mean of 3-5% in human feces; in both cases MM-419447 was the predominant peptide recovered. MM-419447 exhibits high-affinity binding in vitro to T84 cells, resulting in a significant, concentration-dependent accumulation of intracellular cyclic guanosine-3',5'-monophosphate (cGMP). In rat models of gastrointestinal function, orally dosed MM-419447 significantly increased fluid secretion into small intestinal loops, increased intraluminal cGMP, and caused a dose-dependent acceleration in gastrointestinal transit. These results demonstrate the importance of the active metabolite in contributing to linaclotide's pharmacology.
IDENTIFICATION AND USE: Linaclotide is a white to off-white powder. Linaclotide is used in adults in adults for the treatment of irritable bowel syndrome with constipation. It is also used in adults for the treatment of chronic idiopathic constipation. HUMAN EXPOSURE AND TOXICITY: There is limited experience with overdose of linaclotide. During the clinical development program of linaclotide, single doses of 2897 ug were administered to 22 healthy volunteers; the safety profile in these subjects was consistent with that in the overall linaclotide-treated population, with diarrhea being the most commonly reported adverse reaction. Linaclotide is contraindicated in infants and children younger than 6 years of age and should be avoided in children and adolescents 6-17 years of age. While safety and effectiveness has not been established in pediatric patients less than 18 years of age, linaclotide caused deaths in young juvenile mice when administered in single, clinically relevant, adult oral doses. Linaclotide was not genotoxic in the in vitro chromosomal aberration assay in cultured human peripheral blood lymphocytes. ANIMAL STUDIES: In rats, there was no detectable systemic exposure to linaclotide at single oral dose levels of up to 5.0 mg/kg. There were no linaclotide-related effects observed on survival, body weight, food consumption, clinical observations, or macroscopic evaluations. Cynomolgus monkeys were administered a single oral dose of linaclotide at dose levels of 0.5, 1.5, 3.0, and 5.0 mg/kg. The monkeys that were administered a single oral dose of linaclotide (1.5 mg/kg or greater) exhibited changes in stool consistency (non-formed and/or liquid feces), qualitatively reduced food consumption, and/or abdominal distention. There were no significant changes in individual body weight data for these animals. A monkey dosed orally for five consecutive days at 1.5 mg/kg/day exhibited non-formed and liquid feces over the course of the dosing period, with mild abdominal distention occurring on the fourth dosing day. These results demonstrated that linaclotide was well tolerated by Cynomolgus monkeys following a single oral dose at dose levels up to 5.0 mg/kg. However, deaths in juvenile mice were seen when linaclotide was administered in clinically relevant adult doses. In neonatal mice, linaclotide caused deaths at 10 ug/kg/day after oral administration of 1 or 2 daily doses on post-natal day 7. These deaths were due to rapid and severe dehydration. Supplemental subcutaneous fluid administration prevented death after linaclotide administration in neonatal mice. In studies conducted without supplemental fluid administration, tolerability to linaclotide increases with age in juvenile mice. In 2-week-old mice, linaclotide was well tolerated at a dose of 50 ug/kg/day, but deaths occurred after a single oral dose of 100 ug/kg. In 3-week-old mice, linaclotide was well tolerated at 100 ug/kg/day, but deaths occurred after a single oral dose of 600 ug/kg. Linaclotide was well tolerated and did not cause death in 4-week-old juvenile mice at a dose of 1,000 ug/kg/day for 7 days and in 6-week-old juvenile mice at a dose of 20,000 ug/kg/day for 28 days. The potential for linaclotide to cause teratogenic effects was studied in rats, rabbits and mice. Oral administration of up to 100 mg/kg/day in rats and 40 mg/kg/day in rabbits produced no maternal toxicity and no effects on embryo-fetal development. In mice, oral dose levels of at least 40 mg/kg/day produced severe maternal toxicity including death, reduction of gravid uterine and fetal weights, and effects on fetal morphology. Oral doses of 5 mg/kg/day did not produce maternal toxicity or any adverse effects on embryo-fetal development in mice. Linaclotide had no effect on fertility or reproductive function in male and female rats at oral doses of up to 100,000 ug/kg/day. Linaclotide was not genotoxic in an in vitro bacterial reverse mutation (Ames) assay.
In clinical trials, linaclotide therapy was not associated with significant changes in serum enzyme levels or episodes of clinically apparent liver injury. Minor transient ALT elevations arose in
/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/
/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/
来源:Hazardous Substances Data Bank (HSDB)
毒理性
解毒与急救
/SRP:/ 高级治疗：对于昏迷、严重肺水肿或严重呼吸困难的病人，考虑进行口咽或鼻咽气管插管以控制气道。使用气囊面罩装置的正压通气技术可能有益。考虑使用药物治疗肺水肿……。对于严重的支气管痉挛，考虑给予β激动剂，如沙丁胺醇……。监测心率和必要时治疗心律失常……。开始静脉输注D5W TKO /SRP: "保持开放"，最低流量/。如果出现低血容量的迹象，使用0.9%生理盐水（NS）或乳酸钠林格氏液（LR）。对于伴有低血容量迹象的低血压，谨慎给予液体。注意液体过载的迹象……。用地西泮或劳拉西泮治疗癫痫……。使用丙美卡因氢氯化物协助眼部冲洗……。/毒物A和B/
/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W TKO /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's (LR) if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/
来源:Hazardous Substances Data Bank (HSDB)
吸收、分配和排泄
由于在治疗性口服剂量后无法测量利那洛肽的血浆浓度，因此预期利那洛肽在组织中的分布将极为有限。
Given that linaclotide plasma concentrations following therapeutic oral doses are not measurable, linaclotide is expected to be minimally distributed to tissues.
Active peptide recovery in the stool samples of fed and fasted subjects following the daily administration of 290 mcg of Linzess for seven days averaged about 5% (fasted) and about 3% (fed) and virtually all as the active metabolite.
Linzess is minimally absorbed with low systemic availability following oral administration. Concentrations of linaclotide and its active metabolite in plasma are below the limit of quantitation after oral doses of 145 ug or 290 ug were administered. Therefore, standard pharmacokinetic parameters such as area under the curve (AUC), maximum concentration (Cmax), and half-life cannot be calculated.
来源:Hazardous Substances Data Bank (HSDB)
吸收、分配和排泄
尚不清楚利那洛肽是否分布到人乳中。
It is not known whether linaclotide is distributed into human milk.
