SSTR2/3/5

In HepG2 cells, octreotide reverses PA-induced Akt and GSK3β phosphorylation as well as alterations in the expression of GS mRNA [1]. Increased glycogen and phosphorylated glycogen synthase switching 3β (GSK3β) are the results of octreotide (10 8mM, 6 hours).

In the HFD dynamic group, octreotide dramatically lowered insulin concentrations. Octreotide was found to dramatically lower insulin concentrations, but not serum TG, TC, FFA, ALT, or AST levels. The HOMA index is severely inhibited by octreotide. The AUC of ipGTT and ipITT was somewhat reduced by octreotide. In PA-treated HepG2, octreotide reduces steatosis of fat storage caused by HFD cells and lipid droplet accumulation. In HFD fat storage, octreotide stimulates the phosphorylation of Akt and GSK3β as well as the expression of GS mRNA [1]. It also decreased body weight and wet kidney weight in comparison to the crown substance therapy (CONT) group. Treatment with PAS and octreotide/PAS decreased cAMP levels, but octreotide by itself did not lower PCK. The number of pS6-positive cells was considerably lower in the octreotide/PAS group than in the PAS alone group [2].

Western Blot analysis [3]
Cell Types: Human hepatoblastoma HepG2 cell line
Tested Concentrations: 10-8mM
Incubation Duration: 6 hrs (hours)
Experimental Results: The protein expression levels of phospho-Akt and GSK3β increased by 140.8%. and 12.2%, the mRNA levels of GS were also increased.

A total of 24 eligible rats were separated from the HFD group at random and divided into the HFD-control group (n=12) and the octreotide (OCT)-treated group (n=12). These groups were continuously fed a HFD for 8 days, and rats in the octreotide-treated group were subcutaneously injected with octreotide at a dose of 40 µg/kg body weight every 12 h for 8 days. During the octreotide administration period, body weight and food intake were monitored daily. At the end of the experiment, all rats underwent a 12-h starvation period and were sacrificed with 2% sodium pentobarbital (45 mg/kg body weight) administered intraperitoneally. Following sacrifice, blood samples were collected and centrifuged at 860 × g for 15 min at 4°C, and the supernatant was stored at −80°C for further analysis. The liver tissues were isolated, and one sample was rapidly frozen in liquid nitrogen prior to storage at −80°C for total RNA and protein extraction or Oil Red O staining. A second sample was fixed in 4% paraformaldehyde for 48 h at room temperature for histological examination. Abdominal fat was also collected and weighed.[1]

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Male PCK rats (n = 24) were assigned randomly to 1 of 4 groups (n = 6 per group): treatment by subcutaneous injection every 4 weeks treatment with 8 mg/kg octreotide (OCT)-LAR alone, 8 mg/kg PAS-LAR alone, co-application of 8 mg/kg OCT and 8 mg/kg PAS, or vehicle (microparticles liquid; CONT) from 4 to 16 weeks of age. The vehicle contains copolymer microparticles with polylactic-co-glycolic acid (PLGA), obtained from Novartis. In 4- and 15-week-old conscious rats, heart rate (HR), diastolic blood pressure (DBP), and systolic blood pressure (SBP) were determined using a tail-cuff sphygmomanometer. Twenty-four-hour urine volume and food consumption were measured using metabolic cages after 15.5 weeks of age. After body weight measurement, the animals were anesthetized with sodium pentobarbital at 16 weeks of age, and the kidneys and liver were removed rapidly, causing lethal exsanguination. Total wet kidney weight and wet liver weight were measured, and blood samples were collected for measurements of serum urea nitrogen (SUN), aspartate amino transferase (AST), alanine aminotransferase (ALT), insulin-like growth factor-1 (IGF-1), glucose, insulin, glucagon, and cortisol.[2]

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Animals and Diet:** Male Sprague-Dawley rats (3 weeks old, 40-60 g) were housed under standard conditions. After 7 days acclimation on standard diet, rats were divided into normal diet group (320 kcal/100 g, 4.65% fat, n=12) and HFD group (500 kcal/100 g, 60% fat, n=28) for 24 weeks [1]
.
- **Drug Administration:** Octreotide was administered subcutaneously at 40 μg/kg body weight every 12 hours for 8 days to obese rats (body weight ≥1.4-fold higher than controls). HFD-control group received no treatment [1]
.
- **Monitoring:** Body weight, body length, and tail length were measured weekly. Food intake was monitored daily during octreotide administration [1]
.
- **Glucose and Insulin Tolerance Tests:** After 12 h fasting, rats received intraperitoneal glucose (2.0 g/kg) or insulin (7.5 U/kg). Blood samples were collected from tail vein at 0, 15, 30, 60, and 120 min post-injection. Glucose levels were measured using a glucometer. AUC was calculated using GraphPad Prism [1]
.
- **Sample Collection:** At the end of experiment, rats were fasted for 12 h and sacrificed with 2% sodium pentobarbital (45 mg/kg, i.p.). Blood samples were collected, centrifuged at 860×g for 15 min at 4°C, and serum stored at -80°C. Liver tissues were isolated for histological analysis, RNA/protein extraction, or frozen for Oil Red O staining [1]
.
- **Lee's Index Calculation:** Lee's index = [Body weight (g)¹ᐟ³ × 1000] / body length (cm) [1]
.
- **HOMA Index Calculation:** HOMA index = [FPG (mmol/L) × fasting serum insulin (μU/mL)] / 22.5 [1]
.
- **Liver Histology:** Paraffin-embedded liver sections were stained with H&E for morphological evaluation. Frozen liver sections were stained with Oil Red O for lipid assessment. IOD values were analyzed using Image Pro Plus software [1]
.
- **Hepatic TG Measurement:** Liver tissue (50 mg) was homogenized in chloroform-methanol (2:1), mixed, centrifuged, and supernatant collected. NaCl solution (0.9%) was added, centrifuged, and supernatant dried under nitrogen. Residue was dissolved in 3% Triton X-100 and TG measured using a TG assay kit [1]
.
- **Hepatic FFA Measurement:** Liver tissue (50 mg) was homogenized in PBS, centrifuged at 860×g for 20 min at 4°C. Supernatant protein concentration was measured by BCA assay, and FFA concentration determined using a non-esterified free fatty acids assay kit [1]
.
- **Hepatic Glycogen Measurement:** Liver tissue (50 mg) was homogenized in ice-cold PBS, centrifuged at 14,000×g for 10 min at 4°C. Glycogen concentration in supernatant was measured using an EnzyChrom Glycogen assay kit and normalized to protein concentration [1]
.

Absorption, Distribution and Excretion
Octreotide is completely absorbed after subcutaneous injection. After oral administration of sustained-release capsules, the peak concentration is 33% lower than that after subcutaneous injection. The Cmax after oral administration is 1.67–2.5 hours, while that after subcutaneous injection is only 30 minutes. In patients with acromegaly, the peak concentration is 2.5 mg/nL with 20 mg twice daily, and 5.30 ng/mL with 40 mg twice daily. AUC increases proportionally with dose regardless of the route of administration. After oral administration of octreotide, approximately 32% is excreted in the urine, and 30–40% is excreted in the feces via the liver. Approximately 11% of the unchanged drug remains in the urine, and 2% is recovered from the feces. A pharmacokinetic study showed a volume of distribution of 13.6 L in healthy volunteers. Another pharmacokinetic study showed that the volume of distribution after intravenous administration in healthy volunteers ranged from 18.1 to 30.4 L. The systemic clearance of octreotide was 7–10 L/h. One pharmacokinetic study showed that the total clearance of octreotide was 11.4 L/h. Metabolism/Metabolites Octreotide has been reported to be primarily metabolized in the liver. Biological Half-Life The plasma half-life after subcutaneous injection was estimated to be 0.2 hours. The mean elimination half-life between subcutaneous and oral administration was 2.3 to 2.7 hours, with no statistically significant difference. One pharmacokinetic study showed a plasma half-life of 72 to 113 minutes.

Hepatotoxicity
In a minority of patients receiving octreotide treatment, mild, transient, and asymptomatic elevations in serum transaminase levels may occur; in some patients, transaminase levels remain elevated and worsen over time, potentially requiring discontinuation of the drug. Furthermore, several cases of acute, clinically significant liver injury caused by octreotide have been reported. Liver injury typically occurs within 1 to 6 months of starting treatment, and the incidence may be higher with higher doses. Most cases of liver injury associated with octreotide treatment are asymptomatic and without jaundice, characterized by significantly elevated serum ALT and AST, while serum alkaline phosphatase, GGT, and bilirubin levels are normal or near normal. However, jaundice may occur in some cases, especially after re-administration. There are currently no reports of acute liver failure or bile duct disappearance syndrome associated with octreotide; a characteristic of this injury is rapid improvement after discontinuation of injections or infusions. Several cases of significantly elevated transaminase levels have been reported in neonates and infants with congenital hyperinsulinemia receiving continuous infusion of high-dose octreotide, which rapidly returned to normal upon discontinuation of the drug. Octreotide inhibits gallbladder contraction and reduces bile secretion, and long-term treatment is associated with an increased incidence of high-cholesterol gallstones. Prospective studies have shown that 25% to 65% of acromegaly patients receiving octreotide maintenance therapy develop gallstones (detected by ultrasound), some of whom develop symptomatic gallstones requiring hospitalization and cholecystectomy. Even after cholecystectomy, cholesterol stones can still form in the common bile duct and intrahepatic bile ducts, causing symptoms, sepsis, and even requiring partial hepatectomy. Ursodeoxycholic acid treatment does not appear to prevent gallstone formation during octreotide treatment, although it may be helpful. Octreotide is also associated with acute pancreatitis, possibly due to its inhibitory effect on gastrointestinal hormone release, although other cases may be due to gallstone expulsion and pancreatic duct obstruction. Probability score: C (likely a clinically significant cause of liver damage).

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Effects during pregnancy and lactation
◉ Overview of use during lactation
It has not been studied whether octreotide is excreted into breast milk. However, due to its high molecular weight of 10¹⁹ Daltons, very little is likely excreted into breast milk. It is poorly absorbed orally, but has been safely administered directly to infants by injection, so adverse effects on breastfed infants are unlikely. At least three infants have been successfully breastfed without any reported adverse reactions. Until more data are available, breastfeeding women should use octreotide under close monitoring of their infants, especially if the infant is under 2 months old.
◉ Effects on breastfed infants
One mother received octreotide for acromegaly during pregnancy and postpartum (dosage not specified). She breastfed her infant for 4 months (feeding duration not specified) without any apparent problems.
A woman with acromegaly received long-acting octreotide (Zanderidin LAR; dosage not specified) every 6 weeks postpartum while breastfeeding. Six months postpartum, the injection frequency increased to once every four weeks. She breastfed her infant for 12 months (feeding extent not specified). The child was developing normally at age 5.
◉ Effects on breastfeeding and lactation
A pregnant woman with acromegaly began monthly injections of 10 mg long-acting octreotide at 12 weeks of gestation. After delivery, she continued breastfeeding until 6 weeks postpartum, after which the dose of octreotide LAR needed to be increased to 20 mg per month. She continued to successfully breastfeed while taking octreotide.

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Protein binding
Approximately 65% of the dose is bound to lipoproteins and albumin in plasma.

[1]. Effects of octreotide on hepatic glycogenesis in rats with high fat diet?induced obesity. Mol Med Rep. 2017 Jul;16(1):109-118.

[2]. Beneficial effect of combined treatment with octreotide and pasireotide in PCK rats, an orthologous model of human autosomal recessive polycystic kidney disease. PLoS One. 2017 May 18;12(5):e0177934.

[3]. Effects of octreotide on hepatic glycogenesis in rats with high fat diet‑induced obesity. Mol Med Rep. 2017 Jul;16(1):109-118.

Pharmacodynamics
Octreotide mimics the naturally occurring hormone somatostatin. Similar to somatostatin, it inhibits growth hormone and glucagon, and can be used to treat tissue growth disorders and insulin dysregulation in patients with acromegaly. Furthermore, octreotide can alleviate flushing and diarrhea caused by gastrointestinal tumors by reducing visceral blood flow and various gastrointestinal hormones associated with diarrhea. The product label warns that octreotide may reduce gallbladder contractility, bile secretion, and thyroid-stimulating hormone (TSH) release in healthy volunteers. Additionally, there have been reports of decreased vitamin B12 levels in patients receiving octreotide treatment. Patients taking octreotide should have their vitamin B12 levels closely monitored.

C49H66N10O10S2

1019.24

1018.44

C, 57.74; H, 6.53; N, 13.74; O, 15.70; S, 6.29

83150-76-9

Octreotide acetate;79517-01-4;Octreotide pamoate;135467-16-2

448601

White to off-white solid powder

1.4±0.1 g/cm3

1447.2±65.0 °C at 760 mmHg

153-156

829.1±34.3 °C

0.0±0.3 mmHg at 25°C

1.673

0.77

13

14

17

71

1740

10

C[C@H]([C@H]1C(=O)N[C@@H](CSSC[C@@H](C(=O)N[C@H](C(=O)N[C@@H](C(=O)N[C@H](C(=O)N1)CCCCN)CC2=CNC3=CC=CC=C32)CC4=CC=CC=C4)NC(=O)[C@@H](CC5=CC=CC=C5)N)C(=O)N[C@H](CO)[C@@H](C)O)O

DEQANNDTNATYII-OULOTJBUSA-N

InChI=1S/C49H66N10O10S2/c1-28(61)39(25-60)56-48(68)41-27-71-70-26-40(57-43(63)34(51)21-30-13-5-3-6-14-30)47(67)54-37(22-31-15-7-4-8-16-31)45(65)55-38(23-32-24-52-35-18-10-9-17-33(32)35)46(66)53-36(19-11-12-20-50)44(64)59-42(29(2)62)49(69)58-41/h3-10,13-18,24,28-29,34,36-42,52,60-62H,11-12,19-23,25-27,50-51H2,1-2H3,(H,53,66)(H,54,67)(H,55,65)(H,56,68)(H,57,63)(H,58,69)(H,59,64)/t28-,29-,34-,36+,37+,38-,39-,40+,41+,42+/m1/s1

(4R,7S,10S,13R,16S,19R)-10-(4-aminobutyl)-19-[[(2R)-2-amino-3-phenylpropanoyl]amino]-16-benzyl-N-[(2R,3R)-1,3-dihydroxybutan-2-yl]-7-[(1R)-1-hydroxyethyl]-13-(1H-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentazacycloicosane-4-carboxamide

SMS-201-995; Octreotide; Octreotide-LAR; Longastatin; Octreotide acetate; 83150-76-9; Sandostatin; SMS 201-995; Octreotidum; Octreotida; Octreotide-LAR; .

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: (1). Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture and light.  (2). This product is not stable in solution, please use freshly prepared working solution for optimal results.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

H2O : ~100 mg/mL (~98.11 mM)

Solubility in Formulation 1: 100 mg/mL (98.11 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication.

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