GABAA receptor

Fospropofol, a phosphate ester ater soluble prodrug of propofol has been found to be safe and effective alternative to propofol and midazolam for use in endoscopic and other procedures. The unique pharmacology of fospropofol provides scope for expansion to introduce new drug options for sedation.Fospropofol gets converted to propofol by endothelial alkaline phosphatases5 Propofol is a agonist at GABAA receptor .It binds to a specific site on the a and 11 subunits of the receptor complex, but not to the GABA binding site. Activation of the GABAA receptor results in increased Cl-conductance and hyperpolarization, thus inhibiting the postsynaptic neuron. It also inhibits the excitatory NMDA glutamate receptors thus decreasing Ca++ entry resulting in postsynaptic inhibition. Above mechanisms results in sedation.[1]

A total of 347 (96.3%) and 175 (97.2%) patients in the intervention and control groups, respectively, completed the study. The success rate for the primary outcome was 97.7% for both study drugs. The most frequent AEs in the intervention group were abnormal feeling (62.0%), blood pressure reduction (13.5%), and injection site pain (13.3%). No AEs related to consciousness and mental and cognitive functions or serious adverse events were reported.[2]

Absorption, Distribution and Excretion
Following an intravenous bolus of 10 mg/kg, adequate sedation is achieved within 7 minutes. Recovery from fospropofol-induced sedation takes 21–45 minutes. In healthy subjects, after an intravenous bolus of 6 mg/kg, the pharmacokinetic parameters of fospropofol were as follows: Cmax = 78.7 μg/mL; Tmax = 4 minutes; AUC(0–∞) = 19.0 μg ⋅ h/mL; It is primarily metabolized in the liver to an inactive metabolite, which is then excreted by the kidneys. Renal excretion of unchanged fospropofol is negligible (<0.02%). Fospropofol = 0.33 ± 0.069 L/kg; Propofol metabolite = 5.8 L/kg.
Systemic clearance (CLp), propofol, healthy subjects = 0.28 L/h/kg; CLp, propofol, patients = 0.31 L/h/kg; CLp/F, propofol, healthy subjects or patients = 2.74 L/h/kg.

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Metabolism/Metabolites
Propofol is metabolized by endothelial alkaline phosphatase to propofol, formaldehyde, and phosphate. The metabolite formaldehyde is rapidly oxidized to formic acid by glutathione-dependent and independent dehydrogenases and erythrocytes. Excess formic acid is oxidized to carbon dioxide and excreted via the tetrahydrofolate pathway. Propofol is further metabolized to propofol glucuronide, 4-quinoline sulfate, 1-fluoroquinoline, and 4-glucuronide quinoline. The cytochrome P450 enzyme system does not participate in the metabolism of propofol.

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Biological Half-Life
After administration, the half-lives are as follows: propofol = 0.81 hours; propofol metabolite = 1.13 hours

Effects During Pregnancy and Lactation
◉ Overview of Lactation Use
Currently, there is no information regarding the clinical use of fosprofen during lactation. However, fosprofen is rapidly metabolized into propofol in the body. The amount of propofol in breast milk is extremely low and is not expected to be absorbed by the infant. Although some expert panels recommend suspending breastfeeding for a period of time after propofol administration (specific duration undetermined), most experts recommend resuming breastfeeding once the mother has recovered sufficiently from general anesthesia to breastfeed, without discarding the milk. When multiple anesthetics are used during surgery, the recommendations for the most likely adverse reaction should be followed. General anesthesia for cesarean section using propofol as a component of labor induction may delay the onset of lactation. One study showed that breastfeeding before induction of general anesthesia reduced the need for propofol and sevoflurane compared to breastfeeding mothers who stopped breastfeeding or non-breastfeeding women. Case reports indicate that breast milk turned green after a breastfeeding mother received propofol.
◉ Effects on Breastfed Infants
Four breastfeeding mothers underwent surgery with propofol as part of general anesthesia. All patients also received intravenous remifentanil and rocuronium bromide, and inhaled xenon as part of anesthesia. The target serum concentration of propofol they received was 6.5 mcg/L for induction of anesthesia, and was discontinued upon initiation of xenon inhalation anesthesia. The surgery lasted 35 to 45 minutes. The infants first breastfed at 1.5 hours, 2.8 hours, 4.6 hours, and 5 hours after extubation. No signs of sedation were observed in any of the infants.
◉ Effects on Lactation and Breast Milk
Five women 6 to 15 weeks postpartum received a single intravenous dose of 2 mg midazolam and 2.5 mg/kg propofol, respectively, before general anesthesia. Postoperatively, these women produced less than half the normal milk production of breastfeeding women. The authors hypothesize that the reduced postoperative milk production may be due to perioperative fluid restriction and loss, as well as stress-induced lactation suppression. A woman underwent emergency laparoscopic surgery, during which propofol, fentanyl, remifentanil, mirtazapine, and aminopyrine were administered. Postoperatively, aminopyrine, pyrithione, aminopyrine, butylscopolamine bromide, and metoclopramide were used. Eight hours postoperatively, her breast milk first turned blue-green, then green. Both propofol and metoclopramide can cause green urine. Thirty hours after the milk color change, propofol was detected in the breast milk, but metoclopramide was not detected. A randomized study compared the effects of cesarean section under general anesthesia, spinal anesthesia, or epidural anesthesia versus normal vaginal delivery on serum prolactin and oxytocin levels and the time to lactation initiation. General anesthesia was induced with propofol 2 mg/kg and rocuronium bromide 0.6 mg/kg, followed by sevoflurane and rocuronium bromide 0.15 mg/kg as needed. Fentanyl 1 to 1.5 mcg/kg was administered postpartum. Patients in the general anesthesia group (n = 21) had higher postoperative prolactin levels and a longer mean time to lactation initiation (25 hours) than other groups (10.8 to 11.8 hours). Postpartum oxytocin levels were higher in the non-pharmacological vaginal delivery group than in the general anesthesia and spinal anesthesia groups. A randomized, double-blind study compared the effects of intravenous propofol 0.25 mg/kg, ketamine 0.25 mg/kg, ketamine 25 mg plus propofol 25 mg, and placebo saline on postpartum analgesia after cesarean section. A single dose was administered immediately after umbilical cord ligation. The time to first breastfeeding was 58 minutes in the placebo group, 42.6 minutes in the propofol group, and 25.8 minutes in the propofol plus ketamine group. The time to first breastfeeding was significantly shorter in the combination therapy group than in the other groups. A retrospective study compared women undergoing elective cesarean sections at a hospital in Turkey, including women receiving bupivacaine spinal anesthesia (n = 170) and women receiving general anesthesia (n = 78). General anesthesia was induced with propofol, maintained with sevoflurane, and administered postpartum fentanyl. There was no difference in breastfeeding rates between the two groups at 1 hour and 24 hours postpartum. However, at 6 months postpartum, 67% of women in the general anesthesia group were still breastfeeding, compared to 81% in the spinal anesthesia group—a statistically significant difference. A woman who breastfed 6 to 8 times daily and was nursing an 8-month-old infant was admitted for an appendectomy. During the surgery, she received cefazolin, granisetron, ketorolac, rocuronium, succinylcholine, and sufentanil. The patient also received two intravenous boluses of 150 mg propofol, followed shortly by an intravenous bolus of 50 mg propofol. Post-operatively, she took acetaminophen, cefazolin, ibuprofen, and pantoprazole, and oxycodone and dimenhydrinate as needed. Twenty-two hours post-operatively, the mother expressed her first breast milk, which was light green. Analysis of the green milk using an unverified detection method did not detect propofol. On the fourth day post-operatively, when she resumed breastfeeding, the green color gradually faded and disappeared. The authors believe the green color was likely caused by propofol or its metabolites. A pregnant woman underwent an emergency cesarean section at 24 weeks of gestation. During the procedure, she received 200 mg of propofol and cefazolin and acetaminophen post-delivery. Twelve hours post-operatively, the mother's first expressed breast milk was dark green. Thirty hours post-operatively, the milk turned light green and returned to its normal color after 48 hours.

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Protein Binding
Fosfopropofol and its active metabolite propofol are highly bound to proteins (approximately 98%), primarily albumin. Fosfopropofol does not affect the binding of propofol to albumin.

[1]. J Anaesthesiol Clin Pharmacol. 2011 Jan-Mar; 27(1): 79–83.
[2]. Front Pharmacol. 2021; 12: 687894.
[3]. A double-blind, randomized, multicenter, dose-ranging study to evaluate the safety and efficacy of fospropofol disodium as an intravenous sedative for colonoscopy in high-risk populations. Am J Ther. 2013 Mar-Apr;20(2):163-71.

Propofol is an alkylbenzene compound. Propofol is a Schedule IV controlled substance under the U.S. Drug Enforcement Administration (DEA). Schedule IV controlled substances are less likely to be abused compared to Schedule III controlled substances. It is a sedative. Propofol is a water-soluble prodrug that is converted to propofol in the liver. Propofol is a short-acting hypnotic/sedative/anesthetic. Unlike propofol, fosfoprofol does not cause injection site pain because it does not activate TRPA1 receptors. It was approved by the FDA in December 2008. Under the Controlled Substances Act, fosfoprofol is a Schedule IV controlled substance in the United States. Drug Indications: Used for monitoring anesthetic care, providing sedation to patients undergoing diagnostic procedures such as bronchoscopy and colonoscopy, or minor surgical procedures such as arthroscopy and hallux valgus resection.
FDA Label
Mechanism of Action
Fosprofestophenol is converted to propofol in vivo by endothelial alkaline phosphatase. Propofol crosses the blood-brain barrier, binds to GABA-A receptors, and exerts its agonist effect. By binding to GABA-A receptors, fosprofestophenol increases chloride ion conductance, thereby inhibiting the generation of new action potentials in postsynaptic neurons.
Pharmacodynamics
Fosprofestophenol is a prodrug of propofol, a sedative-hypnotic drug. Unlike propofol, fosprofestophenol is water-soluble and can be administered in aqueous solution. The molar equivalent of 1.86 mg fosprofestophenol is 1 mg propofol.

C13H21O5P

288.27664

288.113

258516-89-1

258516-89-1(Free acid);258516-87-9(Disodium)

3038498

Typically exists as solid at room temperature

3.379

2

5

6

19

296

0

OP(OCOC1C(C(C)C)=CC=CC=1C(C)C)(O)=O

QVNNONOFASOXQV-UHFFFAOYSA-N

InChI=1S/C13H21O5P/c1-9(2)11-6-5-7-12(10(3)4)13(11)17-8-18-19(14,15)16/h5-7,9-10H,8H2,1-4H3,(H2,14,15,16)

[2,6-di(propan-2-yl)phenoxy]methyl dihydrogen phosphate

Fospropofol; [2,6-di(propan-2-yl)phenoxy]methyl dihydrogen phosphate; LZ257RZP7K

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

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

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*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.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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