In epidermal cultures, guaifenesin (2 or 20 µg/mL, 6-48 hours) decreases the release of viscosin [3]. In primary epithelial cells, guaifenesin (10-300 μM, 3-24) decreases the activity of IL-13 inductors and the amount of MUC5AC [4].

AUC values of 2469 (facial) and 711 (iv) μg·min/mL were observed for guaifenesin (50 mg/kg, facial; or 10 mg/kg, intravenous; IV), with t1/2 values of 45.6 hours (facial) and 49.0 hours (iv)[5].

Absorption, Distribution and Excretion
Studies have shown that guaiacol is well absorbed in the gastrointestinal tract after oral administration. Following administration, guaiacol is metabolized, with the majority excreted in the urine. The geometric mean apparent volume of distribution of guaiacol in healthy adult subjects was 116 liters (coefficient of variation CV = 45.7%). The mean clearance of guaiacol was approximately 94.8 liters/hour (coefficient of variation CV = 51.4%). It is readily absorbed from the gastrointestinal tract. It is currently unknown whether guaiacol is distributed into breast milk. It is primarily excreted via the kidneys as inactive metabolites. Five donkeys and three horses were administered guaiacol via gravity intravenous injection until they collapsed. The time and dose required to induce collapse, as well as the time required to return to sternal recumbency and standing, were recorded. Blood samples were collected at 10, 20, 30, 40, 50, and 60 minutes and 2, 3, 4, and 6 hours after administration for guaiacole determination. Serum guaiacole concentrations were analyzed by high-performance liquid chromatography (HPLC), and pharmacokinetic parameters were calculated using computer software. In donkeys, heart rate, respiratory rate, and blood pressure were recorded before and every 5 minutes during recumbency. Arterial blood samples were collected before and every 5 and 15 minutes during recumbency for pH, CO₂, and O₂ analysis. Dynamic data were assessed using analysis of variance (ANOVA), and pharmacokinetic parameters were assessed using t-tests. Respiratory rate decreased significantly during recumbency, but other parameters did not change significantly from baseline. The mean (± standard deviation) recumbency doses for donkeys and horses were 131 mg/kg (27) and 211 mg/kg (8), respectively. The time (minutes) required to return to sternal recumbency was 15 (standard deviation, 11) for donkeys and 34 (standard deviation, 1.4) for horses. The time required for donkeys to regain a standing position was 32 minutes and 36 minutes for horses. The AUC (area under the concentration-time curve, μg/mL, dose-dependent variable) was 231 (standard deviation, 33) for donkeys and 688 (standard deviation, 110) for horses. The clearance rate (CL, mL/h·kg) was 546 (standard deviation, 73), significantly different from the 313 (standard deviation, 62) for horses. The mean residence time (MRT) (hours) was 1.2 (standard deviation, 0.1) for donkeys and 2.6 (standard deviation, 0.5) for horses. The volume of distribution (Vd) (area, mL/kg) was 678 (standard deviation, 92) for donkeys and 794 (standard deviation, 25) for horses. At the dosing rates observed in this study, the dose of guaiacol required to induce a lying down was lower in donkeys than in horses, but their clearance rate was faster.

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Metabolic/Metabolic Products
After oral administration of 400 mg guaiacol, the drug is rapidly hydrolyzed (more than 60% of the dose is hydrolyzed within 7 hours), with the main urinary metabolite being β-(2-methoxyphenoxy)-lactic acid, but the parent drug was not detected in the urine. Furthermore, oxidation and demethylation of guaiacol were observed. Specifically, the drug is primarily metabolized in the liver to β-(2-methoxyphenoxy)-lactic acid. In addition, guaiacol is demethylated by O-demethylases in hepatic microsomes, such that approximately 40% of the administered dose is excreted in the urine as this metabolite within 3 hours. Indeed, O-demethylases appear to be the main enzyme in the metabolism of guaiacol, with its main metabolites being β-(2-methoxyphenoxy)-lactic acid and demethylated hydroxyguaiacol, neither of which is itself inactive.
The main urinary metabolite is β-(2-methoxyphenoxy)-lactic acid. It is primarily excreted in urine as glucuronic acid and sulfate. The oxidative O-demethylation of guaiacol ester ether in male rats after intraperitoneal injection is much faster than in female rats. This metabolic sex difference is consistent with the corresponding difference in O-demethylase activity between male and female animals. It is rapidly hydrolyzed (60% within 7 hours) and then excreted in urine, with β-(2-methoxyphenoxy)-lactic acid as the main urinary metabolite. Half-life: 1 hour. The plasma half-life of guaiacol ester ether is approximately 1 hour. The plasma half-life of guaiacol ester ether is 1 hour. Following intraperitoneal injection, the half-life of the centrally acting muscle relaxant guaiacol ester ether is 56.5 minutes in male rats and 88.5 minutes in female rats.

Toxicity Summary
Guacetisal may stimulate gastric vagal receptors and activate efferent parasympathetic reflexes, leading to the secretion of a mucus mixture with lower viscosity from glands. It may induce coughing. This combination may flush away stubborn, clotted mucopurulent material from obstructed small airways, thereby temporarily improving dyspnea or work of breathing. Toxicity Data
Oral LD50 (Rats): 1510 mg/kg Interactions Recent studies have shown that barbiturate-induced enzyme induction significantly reduces the biological half-life of… guaiacol…

[1]. Bennett, S., N. Hoffman, and M. Monga, Ephedrine- and guaifenesin-induced nephrolithiasis. J Altern Complement Med, 2004. 10(6): p. 967-9.

[2]. Effect of guaifenesin on cough reflex sensitivity. Chest. 2003 Dec;124(6):2178-81.

[3]. Effect of guaifenesin on mucin production, rheology, and mucociliary transport in differentiated human airway epithelial cells. Exp Lung Res. 2011 Dec;37(10):606-14.

[4]. Effects of guaifenesin, N-acetylcysteine, and ambroxol on MUC5AC and mucociliary transport in primary differentiated human tracheal-bronchial cells. Respir Res. 2012 Oct 31;13(1):98.

[5]. Effect of mode of administration on guaifenesin pharmacokinetics and expectorant action in the rat model. Pulm Pharmacol Ther. 2009 Jun;22(3):260-5.

Therapeutic Uses
Expectorant Guacetisal is indicated for the temporary relief of cough symptoms caused by mild upper respiratory tract infections and related conditions such as sinusitis, pharyngitis, and bronchitis, especially when accompanied by thick sputum and nasal congestion. However, its efficacy remains controversial due to very limited supporting data. /US Product Label Content/ Veterinary Drug Description: Guacetisal (glyceryl guaiacolate) is a centrally acting muscle relaxant believed to inhibit or block the transmission of nerve impulses at the level of interneurons in the subcortical regions of the brain, brainstem, and spinal cord. It also has mild analgesic and sedative effects. Guacetisal can be administered intravenously to induce muscle relaxation as an adjunct to short-term surgical anesthesia. It relaxes the muscles of the throat and pharynx, making intubation easier, but has minimal effect on the diaphragm and respiratory function. It may cause a transient increase in heart rate and a decrease in blood pressure. It is also used to treat horses with exercise-induced rhabdomyolysis and dogs with strychnine poisoning.
Veterinarian: This drug is used intravenously in horses as a skeletal muscle relaxant. /Gecolate, Glycodex Injection/

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Drug Warning
The Centers for Disease Control and Prevention (CDC) has published a Morbidity and Mortality Weekly Report (MMWR) describing three cases in the United States where infants under 12 months of age died from taking cough and cold medicines, including Guacetisal. The coroner or medical examiner determined that these drugs were the underlying cause of death. The cases described in this report highlight the need for caution in clinicians when prescribing cough and cold medicines to children under 2 years of age, and for caregivers when administering such medications.
Doping with Guacetisal at doses exceeding the expectorant dosage may cause vomiting, but gastrointestinal upset at regular doses is rare.
Unless directed by a physician, this medication should not be used to treat persistent or chronic coughs, such as those caused by smoking, asthma, chronic bronchitis, or emphysema, or coughs with copious amounts of sputum. A persistent cough may indicate a serious illness. If a cough persists for more than a week, recurs, or is accompanied by fever, rash, or persistent headache, consult a doctor. Adverse reactions…require medical attention only if persistent or bothersome…occur infrequently or rarely, including: diarrhea; dizziness; headache; nausea or vomiting; rash; stomach pain; hives (urticaria). For more complete data on drug warnings for Guacetisal (7 of 7), please visit the HSDB record page. Pharmacodynamics: Guacetisal is an expectorant that works by reducing the adhesion and surface tension of sputum and bronchial secretions, thereby increasing their expectoration. Additionally, Guacetisal promotes the secretion of less viscous gastric juices, which in turn promotes ciliary movement—all these effects ultimately transform a dry, phlegm-free cough into a cough with phlegm that is less frequent. Essentially, Guacetisal enhances the effectiveness of mucociliary movement in clearing accumulated secretions from the upper and lower respiratory tracts by reducing the viscosity and adhesion of these secretions.

C10H14O4

198.22

198.089

93-14-1

Guaifenesin-d3;1189924-85-3;Guaifenesin-d5;1329563-41-8

3516

White to off-white solid powder

1.2±0.1 g/cm3

356.8±27.0 °C at 760 mmHg

77-81 °C

169.6±23.7 °C

0.0±0.8 mmHg at 25°C

1.538

0.57

2

4

5

14

151

0

HSRJKNPTNIJEKV-UHFFFAOYSA-N

InChI=1S/C10H14O4/c1-13-9-4-2-3-5-10(9)14-7-8(12)6-11/h2-5,8,11-12H,6-7H2,1H3

3-(2-methoxyphenoxy)propane-1,2-diol

Guaiacol glyceryl ether; Guaiphenesin; Guaifenesin

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)

DMSO : ~100 mg/mL (~504.49 mM)

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.)