Linaclotide is metabolized within the gastrointestinal tract to its principal, active metabolite, MM-419447, 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.
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.
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
Most common adverse reactions (incidence of at least 2%) reported in IBS-C or CIC patients are diarrhea, abdominal pain, flatulence and abdominal distension.
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.
/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/
When taken orally, linaclotide is not absorbed into the systemic. No detectable levels of linaclotide or its active metabolite were noted after doses of 125 mcg or 290 mcg were administered.
Linaclotide is eliminated fecally (3 - 5% as active metabolites). However most of the dose undergoes proteolysis (processes include reduction of disulfide bonds) in the intestine before being excreted via feces.
来源:DrugBank
吸收、分配和排泄
分布容积
由于在治疗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.
来源:DrugBank
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.
Disclosed are methods of isolating linaclotide, a cyclized 14-amino-acid peptide with three disulfide bonds. The sequence consists of Cys-Cys-Glu-Tyr-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr with disulfide bridges between the cysteine residues at positions 1 and 6, 2 and 10, and 5 and 13. The drug acts as a GCC superagonist, elevating intracellular cGMP composition for treating various disorders, including gastrointestinal disorders, obesity, congestive heart failure and benign prostatic hyperplasia.
Phosphine-Dependent Photoinitiation of Alkyl Thiols under Near-UV Light Facilitates User-Friendly Peptide Desulfurization
作者：Naresh M. Venneti、Ganesh Samala、Rana M. I. Morsy、Lawrence G. Mendoza、Albert Isidro-Llobet、Janine K. Tom、Subha Mukherjee、Michael E. Kopach、Jennifer L. Stockdill
DOI：10.1021/jacs.2c10625
日期：2023.1.18
excesses of phosphine reagents and thiol additives or low-abundance metal catalysts. Here, we report a phosphine-only photodesulfurization (POP) using near-UV light that is clean, high-yielding, and requires as little as 1.2 equiv phosphine. The user-friendly reaction gives complete control to the chemist, allowing solvent and reagent selection based on starting material and phosphine solubility. It
肽作为药物靶点的重要性正在稳步上升，因此迫切需要高效、绿色的制备方法。合成工具箱中的一个关键缺陷是缺乏工业上可行的肽脱硫方法。如果没有这个工具，通常用于组装多肽和蛋白质的强大的天然化学连接反应仍然无法用于药物靶点的工业制备。目前的脱硫方法需要大量过量的膦试剂和硫醇添加剂或低丰度金属催化剂。在这里，我们报告了一种使用清洁、高产且低至 1.2 当量磷化氢的近紫外光的仅磷化氢光脱硫 (POP)。用户友好的反应给化学家完全控制，允许根据起始材料和膦溶解度选择溶剂和试剂。它可以在一系列溶剂中进行，包括水或缓冲液、受保护或未受保护的肽、低稀释度或高稀释度以及克规模。易氧化的氨基酸、π键、芳香环、硫胺键、硫酯和聚糖都对 POP 反应稳定。我们强调了这种方法对工业相关目标脱硫的效用，包括环肽和胰高血糖素样肽 1 (GLP-1(7-36))。该方法还与 NCL 缓冲液兼容，我们通过利那洛肽、抑肽酶和小麦蛋白
A New Regioselective Synthesis of the Cysteine-Rich Peptide Linaclotide
Linaclotide is a 14-amino acid residue peptide approved by the FDA for the treatment of irritable bowel syndrome with constipation (IBS-C), which activates guanylate cyclase C to accelerate intestinal transit. Here we show a new method for the synthesis of linaclotide through the completely selective formation of three disulfide bonds in satisfactory overall yields via mild oxidation reactions of the
利那洛肽是一种 14 氨基酸残基肽，经 FDA 批准用于治疗便秘型肠易激综合征 (IBS-C)，可激活鸟苷酸环化酶 C 以加速肠道转运。在这里，我们展示了一种通过固相和液相的温和氧化反应完全选择性地形成三个二硫键以令人满意的总收率合成利那洛肽的新方法，使用 4-甲氧基三苯甲基 (Mmt)、二苯甲基 (Dpm) 和 2 -硝基苄基 (O-NBn) 保护基团的半胱氨酸分别作为底物。
