SSTR2/3/5

Octreotide-treated groups demonstrate a substantially lower tumor volume in comparison to the saline group. Greater antitumor effect is shown by Octreotide-PPSG (1.4 mg/kg, i.p.) compared to Octreotide-soln (100 μg/kg, i.p.). When comparing the saline group to the primary HCC-bearing rats, octreotide treatments significantly inhibit the expression levels of SSTR2 and SSTR5. The results indicate that the Octreotide-PPSG group appears to inhibit SSTR2 and SSTR5 expression more than the Octreotide-soln treated group[1]. The serum level of gastrin is significantly reduced to around one-third of the baseline within two hours after taking an octreotide acetate test dose. This effect lasts for roughly six hours. Day 21: Octreotide acetatea (5 mg intramuscular, q 4 wk) is administered as part of a sustained-release formulation[2].

Tumor volume was significantly reduced in the octreotide-treated group compared with the saline group. Octreotide-PPSG (1.4 mg/kg, i.p.) showed stronger antitumor effects than octreotide-solution (100 μg/kg, i.p.). Compared with the saline group, octreotide treatment had a significant inhibitory effect on the expression levels of SSTR2 and SSTR5 in primary HCC rats. Octreotide-PPSG seems to inhibit the expression of SSTR2 and SSTR5 more than the octreotide solution treatment group [1]. Test doses of octreotide acetate significantly reduced serum gastrin levels to approximately one-third of baseline within 2 hours, with effects lasting approximately 6 hours. On day 21, treatment with octreotide acetate extended-release formulation (5 mg intramuscularly, once every 4 weeks) was initiated [2].

Western Blot analysis [1]
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.

Mice: Three groups are randomly assigned to thirty mice bearing HCC xenografts: (A) Octreotide-soln group; (B) Octreotide-PPSG group; and (C) control group. The octreotide-soln group is given an intraperitoneal injection (i.p.) of 100 μg/kg octreotide-soln once a day for 14 days in a row. The Octreotide-PPSG group is administered a single subcutaneous injection with a volume of approximately 0.2 mL, containing 1.4 mg/kg of Octreotide-PPSG. Saline is injected intraperitoneally (i.p.) once daily for a total of 14 days to the control group. Following injection of H22 hepatoma cell suspension, treatment begins the following day and lasts for 14 days. Periodic caliper measurements are used to track the growth of tumors on days 7 and 14 after seeding. Equation can be used to calculate tumor volumes (V) from the tumor's length and width.
Rats: Two groups of twelve male SD rats are placed in standard cages at 25°C with free access to food and water one week before the experiment. Octreotide-PPSG or Octreotide-soln, at a single dose equivalent to 20 mg/kg, are injected subcutaneously into rats. The clinical dose of octreotide-soln in humans is used to calculate the dosage. The food is given back to the rats about two hours after the dosage, and they fast for twelve hours before. Heparinized Eppendorf tubes are used to collect blood samples at prearranged intervals. The blood samples are immediately placed on ice and centrifuged at 3000 g for 10 min in less than an hour after collection. Prior to analysis, the plasma is gathered and kept at -20°C.

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]. Pharmacokinetic and pharmacodynamic study of a phospholipid-based phase separation gel for once a month administration of octreotide. J Control Release. 2016 May 28;230:45-56.

[2]. Treatment of Gastrin-Secreting Tumor With Sustained-Release Octreotide Acetate in a Dog. J Am Anim Hosp Assoc. 2015 Nov-Dec;51(6):407-12.

[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.

C51H70N10O12S2

1079.29

1078.461

C, 55.92; H, 6.48; N, 11.86; O, 20.31; S, 5.43

79517-01-4

Octreotide; 83150-76-9; 1607842-55-6 (HCl); 135467-16-2 (Octreotide pamoate)

448601

White to off-white solid powder

1.4±0.1 g/cm3

1447.2±65.0 °C at 760 mmHg

153-156ºC

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 acetate; Sandostatin; SMS 201-995; Octreotidum; Octreotida; 79517-01-4; Octreotide acetate

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture and light.

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

DMSO: ~250 mg/mL (~231.6 mM)
H2O: ~25 mg/mL (~23.2 mM)

Solubility in Formulation 1: ≥ 2.25 mg/mL (2.08 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 22.5 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.25 mg/mL (2.08 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 22.5 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.25 mg/mL (2.08 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 22.5 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: 100 mg/mL (92.65 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication.

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