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
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]. 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 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.

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.)