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 guaifenesin is well absorbed from and along the gastrointestinal tract after oral administration.
After administration, guaifenesin is metabolized and then largely excreted in the urine.
The geometric mean apparent volume of distribution of guaifenesin determined in healthy adult subjects is 116L (CV=45.7%).
The mean clearance recorded for guaifenesin is about 94.8 L/hr (CV=51.4%).
Readily absorbed from the gastrointestinal tract.
It is not known whether guaifenesin is distributed into breast milk.
Elimination /is/ renal, as inactive metabolites.
Five donkeys and three horses were given guaifenesin, intravenously, by gravity administration, until recumbency was produced. The time and dose required to produce recumbency, recovery time to sternal and standing were recorded. Blood samples were collected for guaifenesin assay at 10, 20, 30, 40, 50, 60 min, and 2, 3, 4 and 6 hr after guaifenesin administration. Serum was analysed for guaifenesin using HPLC and pharmacokinetic values were calculated using a computer software package. In donkeys, heart and respiratory rates and blood pressures were recorded before and at 5-min intervals during recumbency. Arterial blood samples were collected before and at 5 and 15 min intervals during recumbency for analysis of pH, CO2, and O2. ANOVA was used to evaluate dynamic data, while t-tests were used for kinetic values. Respiratory rate was decreased significantly during recumbency, but no other significant changes from baseline occurred. The mean (+/- SD) recumbency dose of guaifenesin was 131 mg/kg (27) for donkeys and 211 mg/kg (8) for horses. Recovery time to sternal (min) was 15 (SD, 11) for donkeys and 34 (SD, 1.4) for horses. Time to standing was 32 min for donkeys and 36 min for horses. Calculation of AUC (area under the concentration-time curve) microgram/mL) (dose-dependent variable) was 231 (SD, 33) for donkeys and 688 (SD, 110) for horses. The clearance (CL) (mL/hr.kg) was 546 (SD, 73) for donkeys, which was significantly different from 313 (SD, 62) for horses. Mean residence time (MRT) (hr) was 1.2 (SD, 0.1) for donkeys and 2.6 (SD, 0.5) for horses. Volume of distribution Vd(area) (mL/kg) was 678 (SD, 92) for donkeys and 794 (SD, 25) for horses. At the rate of administration used in this study, donkeys required less guaifenesin than horses to produce recumbency, but cleared it more rapidly.

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Metabolism / Metabolites
After the oral administration of 400 mg guaifenesin, the agent experiences rapid hydrolysis (more than 60% of the dose hydrolyzed over a range of seven hours) with β-(2-methoxyphenoxy)-lactic acid found as the major urinary metabolite but no parent drug detectable in the urine. Moreover, it has been observed that guaifenesin also experiences both oxidation and demethylation. In particular, the medication is quickly metabolized hepatically by way of oxidation to β-(2-methoxyphenoxy)-lactic acid. Furthermore, guaifenesin is also demethylated by O-demethylase in liver microsomes to the point where about 40% of an administered dose is excreted as this metabolite in the urine within 3 hours. In fact, O-demethylase appears to be the primary enzyme for the metabolism of guaifenesin and the primary metabolites of the substance are β-(2-methoxyphenoxy)-lactic acid and the demethylated hydroxyguaifenesin, both of which are themselves inactive moieties.
The major urinary metabolite is beta-(2-methoxyphenoxy) lactic acid.
It is excreted in urine principally as glucuronates & sulfates.
Oxidative o-demethylation of glyceryl guaiacolate ether occurred much more rapidly in ip injected male rats than in females. This sex difference in metabolism was paralleled by corresponding difference in o-demethylase activity between male & female animals.
Rapidly hydrolyzed (60% within seven hours) and then excreted in the urine, with beta-(2-methoxyphenoxy)-lactic acid as its major urinary metabolite.
Half Life: 1 hour

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Biological Half-Life
The half-life in plasma observed for guaifenesin is approximately one hour.
Guaifenesin has a plasma half-life of one hour.
Centrally acting muscle relaxant glyceryl guaiacolate ether was found to have t/2 of 56.5 min in male rats and 88.5 min in female rats following ip administration.

Toxicity Summary
Guaifenesin may act as an irritant to gastric vagal receptors, and recruit efferent parasympathetic reflexes that cause glandular exocytosis of a less viscous mucus mixture. Cough may be provoked. This combination may flush tenacious, congealed mucopurulent material from obstructed small airways and lead to a temporary improvement in dyspnea or the work of breathing.

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Toxicity Data
Oral, Rat: LD₅₀ 1510 mg/kg

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Interactions
Enzyme induction due to barbiturates has recently been shown to significantly reduce biological t/2 of...glyceryl guaiacolate ether...

[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
Expectorants
Guaifenesin is indicated as an expectorant in the temporary symptomatic management of cough due to minor upper respiratory infections and related conditions, such as sinusitis, pharyngitis, and bronchitis, when these conditions are complicated by viscous mucus and congestion. However, because supporting data are very limited, there is some controversy about its effectiveness. /Included in US product label/
VET: Guaifenesin (glyceryl guaiacolate) is a centrally acting muscle relaxant that is believed to depress or block nerve impulse transmission at the internuncial neuron level of the subcortical areas of the brain, brain stem, and spinal cord. It also has mild analgesic and sedative actions. Guaifenesin is given IV to induce muscle relaxation as an adjunct to anesthesia for short procedures. It relaxes both laryngeal and pharyngeal muscles, allowing easier intubation, but has little effect on diaphragm and respiratory function. It may cause transient increases in cardiac rate and decreases in blood pressure. It is also used in treatment of horses with exertional rhabdomyolysis and in dogs with strychnine intoxication.
VET: The drug is used intravenously as a skeletal muscle relaxant in horses. /Gecolate, Glycodex Injection/

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Drug Warnings
The Centers for Disease Control and Prevention (CDC) issued a Morbidity and Mortality Weekly Report (MMWR) article describing three deaths in U.S. infants aged less than 12 months associated with cough and cold medications /including guaifenesen/. These medications were determined by medical examiners or coroners to be the underlying cause of death. The cases described in this report underscore the need for clinicians to use caution when prescribing and caregivers to use caution when administering cough and cold medications to children aged less than 2 years.
Doses of guaifenesin larger than those required for expectorant action may produce emesis, but GI upset at ordinary dosage levels is rare.
For self-medication, unless directed by a physician, guaifenesin should not be used for persistent or chronic cough such as that occurring with smoking, asthma, chronic bronchitis, or emphysema, or for cough accompanied by excessive phlegm. A persistent cough may be indicative of a serious condition. If cough persists for more than one week, is recurrent, or is accompanied by fever, rash, or persistent headache, a physician should be consulted.
Adverse effects ... indicating need for medical attention only if they continue or are bothersome ... occurring at an incidence less frequent or rare /include/: diarrhea; dizziness; headache; nausea or vomiting; skin rash; stomach pain; urticaria (hives).
For more Drug Warnings (Complete) data for GUAIFENESIN (7 total), please visit the HSDB record page.

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Pharmacodynamics
Guaifenesin is categorized as an expectorant that acts by enhancing the output of phlegm (sputum) and bronchial secretions via decreasing the adhesiveness and surface tension of such material. Furthermore, guaifenesin elicits an increased flow of less viscous gastric secretions that subsequently promote ciliary action - all actions that ultimately change dry, unproductive coughing to coughs that are more productive and less frequent. Essentially, by decreasing the viscosity and adhesiveness of such secretions, guaifenesin enhances the efficacy of mucociliary activity in removing accumulated secretions from the upper and lower airway.

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.)