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]

Absorption, Distribution and Excretion
After a subcutaneous dose, octreotide is absorbed completely upon administration. After the administration of an oral delayed-release capsule, peak concentrations were found to be 33% lower than after subcutaneous administration. The Cmax was attained at 1.67–2.5 hours after oral administration versus 30 minutes for the subcutaneous route. At 20 mg twice a day in patients with acromegaly, peak concentration was 2.5 mg/nL versus 5.30 ng/mL at 40 mg twice a day. AUC increases in proportion with the dose, regardless of the route.
About 32% of an oral octreotide dose is excreted into the urine and 30-40% is excreted by the liver into the feces.. About 11% of the unchanged parent drug is found in the urine, and 2% of the unchanged parent drug can be recovered in the feces.
In a pharmacokinetic study, the volume of distribution was 13.6 L in healthy volunteers. One pharmacokinetic study revealed a volume of distribution ranging from 18.1-30.4L after intravenous administration in healthy volunteers.
The total body clearance of octreotide is 7-10 L/h. One pharmacokinetic study revealed a total body clearance of 11.4 L/h.

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Metabolism / Metabolites
Octreotide has been reported to be heavily metabolized in the liver.

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Biological Half-Life
After a subcutaneous dose, the plasma half-life is estimated to be 0.2 hours. The average elimination half-lives for subcutaneous and oral administration ranged from 2.3 - 2.7 hours and did not differ significantly. One pharmacokinetic study revealed a plasma half-life ranging from 72-113 minutes.

Hepatotoxicity
Mild, transient, asymptomatic elevations in serum aminotransferase levels occur in a small proportion of patients receiving octreotide, and in some individuals the elevations are persistent and worsen over time and may require drug discontinuation. In addition, several instances of acute, clinically apparent liver injury attributable to octreotide have been described. The onset is generally within 1 to 6 months of starting therapy and injury may be more frequent with higher doses. Most cases of liver injury associated with octreotide therapy have been asymptomatic and anicteric, and marked by prominent elevations in serum ALT and AST with normal or near normal serum alkaline phosphatase, GGT and bilirubin. In some instances, however, jaundice has arisen, particularly with rechallenge. There have been no instances of acute liver failure or vanishing bile duct syndrome associated with octreotide, and a characteristic feature of the injury is the rapidity of improvement upon stopping the injections or infusions. Several instances of marked aminotransferase elevations with rapid improvements on stopping have been reported in newborns and infants with congenital hyperinsulinemia who were treated with continuous infusions of high doses of octreotide.
Octreotide causes inhibition of gall bladder contractility and decrease in bile secretion, and long term therapy is associated with a high rate of cholesterol gallstone formation. In prospective studies, between 25% and 65% of patients with acromegaly treated with maintenance octreotide developed gallstones detected by ultrasonography and a proportion developed symptomatic cholelithiasis requiring hospitalization and cholecystectomy. Even after cholecystectomy, cholesterol stones may form in the common bile duct and intrahepatic ducts causing symptoms, episodes of sepsis and need for partial hepatic resection. Therapy with ursodiol does not appear to prevent gallstone formation during octreotide therapy, although it may help. Octreotide has also been associated with acute pancreatitis, which may be due to its inhibitory effect on gastrointestinal hormone release, although other cases may be secondary to passage of gall bladder stones and pancreatic duct obstruction.
Likelihood score: C (probable cause of clinically apparent liver injury).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
The excretion of octreotide into breastmilk has not been studied. However, because it has a high molecular weight of 1019 daltons it is likely to be poorly excreted into breastmilk. It is poorly absorbed orally and has been safely administered directly to infants by injection, so it is unlikely to adversely affect the breastfed infant. At least 3 infants have been successfully breastfed with no adverse effects reported. Until more data are available, octreotide should be used in nursing mothers with careful infant monitoring, especially if the infant is under 2 months of age.
◉ Effects in Breastfed Infants
One mother was treated for acromegaly during pregnancy and postpartum with octreotide (dose not stated). She breastfed (extent not stated) her infant for 4 months with no apparent problems noted in the infant.
A woman with acromegaly took long-acting octreotide (Sandostatin LAR; dose not stated) every 6 weeks postpartum while breastfeeding. At 6 months postpartum, the frequency of the injections was increased to every 4 weeks. She breastfed her infant (extent not stated) for 12 months. At age 5 years the child had developed normally.
◉ Effects on Lactation and Breastmilk
A pregnant woman with acromegaly started long-acting octreotide 10 mg monthly at 12 weeks gestation. After delivery, she breastfed her until 6 weeks postpartum when she required an increase in octreotide LAR to 20 mg monthly. She continued to breastfeed successfully on octreotide.

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

[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 known as somatostatin. Like somatostatin, it demonstrates activity against growth hormone and glucagon, treating the disordered tissue growth and insulin regulation in patients with acromegaly. In addition, octreotide relieves the flushing and diarrhea associated with gastrointestinal tumors by reducing splanchnic blood flow and various gastrointestinal hormones associated with diarrhea. Product labeling warns that octreotide may reduce gallbladder contractility, bile secretion, and the release of thyroid-stimulating hormone (TSH) in healthy volunteers. In addition, reports of decreased vitamin B12 in patients treated with octreotide have been made. Ensure to monitor vitamin B12 levels in patients taking octreotide.

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.)