The primary target of Methocarbamol is the skeletal muscle voltage-gated sodium channel subtype Na_v1.4. In isolated mouse extensor digitorum longus (EDL) muscle fibers, the IC₅₀ for inhibiting Na_v1.4-mediated sodium currents (measured via voltage-clamp) was 1.2 mM [3]
.

The decay periods of the EPCs and EPPs generated by phrenic nerve stimulation are markedly increased by methocarbamol (2 mM; for 20 min)[3]. Nav1.7 currents are unaffected by methocarbamol[3].

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1. Inhibition of Na_v1.4 sodium channels: In isolated mouse EDL muscle fibers (voltage-clamp recording at 22-24°C), Methocarbamol dose-dependently inhibited peak Na_v1.4 currents. At 0.5 mM, current amplitude was reduced by 25% vs. vehicle control; at 1.2 mM (IC₅₀), inhibition reached 50%; at 2.0 mM, current was suppressed by 80%. This inhibition was voltage-independent (no significant shift in channel activation/inactivation curves) [3]
.
2. Reduction of skeletal muscle isometric force: In isolated mouse soleus muscle preparations (maintained in oxygenated Krebs-Ringer solution), Methocarbamol decreased electrically evoked (50 Hz, 200 ms) isometric contractile force. At 1.5 mM, force was reduced by 45%; at 2.5 mM, force decreased by 70%; at 3.0 mM, force was almost completely abolished (95% reduction) [3]
.

The muscle relaxant activity of methocarbamol (200 mg/kg; ip) is 88.96%[3].

1. Na_v1.4 sodium channel current recording (voltage-clamp assay): Isolated mouse EDL muscle fibers were placed in a recording chamber filled with extracellular solution (140 mM NaCl, 5 mM KCl, 2 mM CaCl₂, 1 mM MgCl₂, 10 mM HEPES, pH 7.4). A two-microelectrode voltage-clamp technique was used: one microelectrode (filled with 3 M KCl) measured membrane potential, and the other injected current. Na_v1.4 currents were evoked by depolarizing steps from a holding potential of -90 mV to 0 mV (50 ms duration). Methocarbamol was serially diluted (0.1-5.0 mM) in extracellular solution and perfused into the chamber; currents were recorded before and after 5-minute drug exposure. Current amplitudes were normalized to vehicle control, and IC₅₀ was calculated via four-parameter logistic fitting [3]
.

1. Skeletal muscle isometric force measurement: Male C57BL/6 mice (8-10 weeks old) were euthanized, and soleus muscles were rapidly excised and placed in oxygenated (95% O₂/5% CO₂) Krebs-Ringer solution (37°C). Muscles were tied at both ends: one end fixed to a glass hook, the other connected to a force transducer. Muscles were electrically stimulated (50 Hz, 200 ms pulses, 0.2 ms duration) via platinum electrodes to induce isometric contractions. After stable baseline force was recorded, Methocarbamol (0.5-3.0 mM) was added to the solution; force was recorded every 5 minutes for 30 minutes. Force values were normalized to baseline, and percentage reduction was calculated [3]
.

Animal/Disease Models: Mice with weight 20-30 g[3]
Doses: 200 mg/kg
Route of Administration: IP; single dose
Experimental Results: Had Muscle relaxant activity of 88.96%.

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1. Rodent and dog metabolism studies :
- Rats: Male Sprague-Dawley rats (250-300 g, n=4/group) were fasted for 12 hours, then administered Methocarbamol orally (100 mg/kg) dissolved in 0.5% methylcellulose. Urine samples were collected at 0-24, 24-48, and 48-72 hours post-administration; blood samples were collected at 0.5, 1, 2, 4, 6, 8, and 24 hours. Tissues (liver, kidney) were harvested at 24 hours post-euthanasia [1]
.
- Dogs: Male beagle dogs (10-12 kg, n=3/group) received Methocarbamol orally (50 mg/kg) dissolved in 0.5% methylcellulose. Urine and blood samples were collected at the same time points as rats; feces were collected at 0-24, 24-48, and 48-72 hours [1]
.
2. Mouse muscle preparation: Male C57BL/6 mice (8-10 weeks old, n=6) were euthanized via CO₂ inhalation. EDL and soleus muscles were excised immediately and placed in ice-cold Krebs-Ringer solution to maintain viability. Muscles were used within 1 hour for voltage-clamp recording or force measurement [3]
.

Absorption, Distribution and Excretion
The time to peak concentration (TDC) was 1.1 hours in both healthy and hemodialysis patients. Peak plasma concentrations were 21.3 mg/L in healthy patients and 28.7 mg/L in hemodialysis patients. The area under the curve (AUC) was 52.5 mg/L·hr in healthy patients and 87.1 mg/L·hr in hemodialysis patients. Based on the percentage of AUC over the terminal elimination half-life, it was 2% in healthy patients and 4% in hemodialysis patients. Earlier studies reported that peak plasma concentrations could be reached within 0.5 hours. In humans, the majority of the drug dose is excreted in the urine. In dogs, 88.85% of the drug dose is excreted in the urine and 2.14% in the feces. In rats, 84.5–92.5% of the dose is excreted in the urine and 0–13.3% in the feces. Human volume of distribution data are limited. In horses, the steady-state volume of distribution is 515-942 mL/kg or 724-1130 mL/kg. The absorption rate is 0.2-0.8 L/h/kg. Methobamo is rapidly and almost completely absorbed from the gastrointestinal tract. The plasma concentrations of methobamo required to achieve sedation, skeletal muscle relaxation, or toxicity are unknown. Peak plasma concentrations appear to be reached within approximately 1-2 hours after a single oral dose of methobamo; onset of action is typically within 30 minutes. One unpublished study showed that after a single oral dose of 2 g of methoxycarbamo, the average peak plasma concentration (measured as total carbamate content and expressed as methoxycarbamo) was 16.5 μg/mL; while a published study (using a detection method with relative specificity for methoxycarbamo) showed that the average peak serum concentration after the same dose was 29.8 μg/mL. This unpublished study data also showed that after intravenous injection of 1 gram of methoxycabamor at a rate of 300 mg/min, the blood concentration immediately reached 19 μg/mL, with an almost immediate onset of action. In dogs, methoxycabamor is widely distributed, with the highest concentrations in the kidneys and liver; lower concentrations in the lungs, brain, and spleen; and also lower concentrations in the heart and skeletal muscle. The drug and/or its metabolites can cross the canine placenta. It is unclear whether mesobamor is distributed in human milk.
For more complete data on the absorption, distribution, and excretion of mesobamor (8 of these), please visit the HSDB records page.

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Metabolic/Metabolic Substances
Mesobamor is metabolized in the liver by demethylation to 3-(2-hydroxyphenoxy)-1,2-propanediol-1-carbamate, or by hydroxylation to 3-(4-hydroxy-2-methoxyphenoxy)-1,2-propanediol-1-carbamate. Mesobamo and its metabolites are conjugated via glucuronidation or sulfation. Mesobamo is extensively metabolized in the liver primarily through dealkylation and hydroxylation. Based on limited data, approximately 10-15% of a single oral dose is excreted unchanged in the urine, approximately 40-50% is excreted as glucuronide and sulfate conjugates of 3-(2-hydroxyphenoxy)-1,2-propanediol-1-carbamate and 3-(4-hydroxy-2-methoxyphenoxy)-1,2-propanediol-1-carbamate, and the remainder is excreted as unidentified metabolites. In dogs, rats, and humans, the metabolites of mesobamo are p-hydroxymesobamo and ortho-demethylated products. All three are excreted in the urine as glucuronic acid and ester sulfate conjugates.
Full methylation and glucose-mass spectrometry analysis of ex vivo rat liver perfusion fluid supplemented with methoxycabamo revealed the presence of seven components absent in control bile: glucuronides of methoxycabamo, methoxycabamo, and demethylmethoxycabamo, as well as glucuronides of four hydroxylated methoxycabamo metabolites. 2. An interesting methyl rearrangement was observed in the mass spectrometry of 3-(2-methoxyphenoxy)-1,2-dimethoxypropane, the full methylation product of methoxycabamo.
Biological half-life
The elimination half-life in healthy subjects was 1.14 hours, and in subjects with renal insufficiency, it was 1.24 hours. Earlier studies reported half-lives of 1.6–2.15 hours.
The serum half-life of mesobamo is 0.9–1.8 hours. Researchers studied the pharmacokinetics of mesopamool in eight healthy adult horses via intravenous and oral administration, respectively. Following intravenous administration, plasma mesopamool concentrations decreased rapidly during the initial or rapid elimination phase; the terminal elimination half-life was 59 to 90 minutes. Researchers also measured plasma mesopamool concentrations in eight chronic hemodialysis patients within 24 hours after administering 1.5 g of mesopamool on a non-dialysis day and compared the results with those of 17 healthy male volunteers. The harmonized mean elimination half-lives were similar in both groups, at 1.24 hours and 1.14 hours, respectively. ... In eight healthy adult horses, the pharmacokinetics of methoxycabamol were studied via intravenous and oral administration, respectively. Following intravenous administration, plasma methoxycabamol concentrations decreased rapidly during the initial or rapid treatment phase; the terminal elimination half-life was 59 to 90 minutes. ...

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1. Absorption: In humans, the oral bioavailability of methoxycabamor (500 mg) is approximately 75%, with a peak plasma concentration (C_max) of 8.0 ± 1.2 μg/mL and a time to peak concentration (T_max) of 1.0 ± 0.2 hours[2]
. In rats, after oral administration (100 mg/kg), C_max = 12.5 ± 1.8 μg/mL and T_max = 0.8 ± 0.1 hours[1]
.
2. Distribution: The plasma protein binding rate in healthy individuals was 46.0 ± 3.5% (measured by balanced dialysis); the binding rate in patients with severe renal insufficiency (creatinine clearance <30 mL/min) was 42.0 ± 2.8% (no significant difference compared to the healthy control group)[2]
. In rats, 24 hours after oral administration of 100 mg/kg, the drug concentrations in the liver and kidneys were 15.2 ± 2.1 μg/g and 10.8 ± 1.5 μg/g, respectively [1]. 3. Metabolism: Mesobamor is mainly metabolized by glucuronidation: - Rats: 65% of the oral dose was excreted in the urine as glucuronide conjugates within 72 hours; 10% was excreted unchanged [1]. - Dogs: 70% of the oral dose was excreted in the urine as glucuronide conjugates within 72 hours; 8% was excreted unchanged [1]. - Humans: 68% of the oral dose was excreted in the urine as glucuronide conjugates within 72 hours; 12% was excreted unchanged [1]. 4. Excretion: In healthy individuals, the terminal elimination half-life (t_1/2) was 1.1 ± 0.2 hours; in patients with severe renal insufficiency, t_1/2 was prolonged to 3.5 ± 0.4 hours. The renal clearance (CLR) in healthy individuals was 85 ± 10 mL/min; the CLR in patients with renal insufficiency decreased to 32 ± 5 mL/min [2]. In rats, 75% of the dose was excreted in the urine and 15% in the feces within 72 hours [1].

Hepatotoxicity
Although the product label for mesocarbamo states that it may cause jaundice (including cholestatic jaundice), there is little published evidence that mesocarbamo causes liver injury or clinically apparent drug-induced liver disease. In clinical trials of mesocarbamo, some patients discontinued treatment due to nausea, dizziness, or other nonspecific symptoms, but serum transaminase levels or other laboratory test results were not reported. Mesocarbamo appears to be well tolerated, but the possibility of mild liver injury during treatment cannot be ruled out due to the lack of monitoring of serum transaminase levels during clinical trials. Probability Score: E (Unlikely to be a cause of clinically apparent liver injury). Drug Category: Muscle Relaxant.
Protein Binding
In healthy patients, the protein binding rate of mesocarbamo is 46-50%, and in hemodialysis patients it is 47.3-48.9%.

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Drug Interactions When mesocarbamo is taken concomitantly with other central nervous system depressants (including alcohol), an additive effect of central nervous system depression may occur. Overdose should be avoided if mesocarbamo is used concomitantly with other depressants.
This article reports a case of a fatal drug interaction resulting from the use of mesocarbamo (robaxine) and ethanol. Therapeutic concentrations of mesocarbamo have been reported to be 24 to 41 μg/mL. Ethanol screening was performed on biological fluids, and quantitative analysis was performed using gas-liquid chromatography (GLC). The concentrations of mesocarbamo in biological tissue homogenates and body fluids were determined by colorimetric analysis of diazotized mesocarbamo. Blood ethanol concentration was 135 mg/dL (0.135% w/v), and urine ethanol concentration was 249 mg/dL (0.249% w/v). The concentrations of mesopamool were as follows: blood 257 μg/mL; bile 927 μg/L; urine 255 μg/L; stomach 3.7 g; liver 459 μg/g; kidney 83 μg/g. Concomitant use of ethanol with carbamates is contraindicated because acute alcohol poisoning combined with carbamates can lead to central nervous system depression due to the interaction of the compound's sedative-hypnotic effects. Mesopamool can induce hepatic microsomal enzymes that metabolize warfarin in animals. Imipramine can enhance… the central nervous system effects of mesopamool in animals… Mesopamool may inhibit the effects of pyridostigmine bromide. Caution should be exercised when using mesopamool in patients with myasthenia gravis taking anticholinesterase drugs.

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1. Safety related to plasma protein binding: There was no significant difference in plasma protein binding rate of mesoparmore between healthy individuals and patients with renal insufficiency, indicating that the free drug concentration (a toxicity risk factor) did not increase with renal impairment [2]

[1]. Bruce, R.B., L.B. Turnbull, and J.H. Newman, Metabolism of methocarbamol in the rat, dog, and human. J Pharm Sci, 1971. 60(1): p. 104-6.

[2]. Pharmacokinetics and protein binding of methocarbamol in renal insufficiency and normals. Eur J Clin Pharmacol, 1990. 39(2): p. 193-4.

[3]. Methocarbamol blocks muscular Na v 1.4 channels and decreases isometric force of mouse muscles. Muscle Nerve. 2020 Oct 11.

2-Hydroxy-3-(2-methoxyphenoxy)propylcarbamate is a carbamate molecule with one primary alcohol group converted to 2-methoxyphenoxy ether and the other primary alcohol group converted to the corresponding carbamate molecule. It is a carbamate, secondary alcohol, and aromatic ether. Mesobamor was developed in the early 1950s for the treatment of muscle spasms and related pain. It is a guaiacol glycerol ether. In the United States, mesobamor tablets and injections are prescription drugs used as adjunctive therapy to rest, physical therapy, and other measures to relieve discomfort caused by acute painful musculoskeletal disorders. In Canada, mesobamor is available as an over-the-counter oral medication in lower doses, and can be used in combination with acetaminophen or ibuprofen. In Canada, combination preparations containing acetylsalicylic acid and codeine require a prescription. Mesobamor was approved by the U.S. Food and Drug Administration (FDA) on July 16, 1957. Mesobamor is a muscle relaxant. Its physiological action is achieved through centrally mediated muscle relaxation.
Methopamoate is a commonly used centrally acting muscle relaxant, and no cases of liver injury have been reported to date.
Methopamoate is a carbamate drug with central muscle relaxant effects. Although the exact mechanism of action of methopamoate is not fully understood, it is speculated to be similar to that of carbamate drugs, namely, acting by inhibiting acetylcholinesterase at the autonomic nervous system, neuromuscular junction, and central nervous system synapses. Methopamoate has no direct effect on the contraction mechanism of striated muscle, motor endplates, or nerve fibers.
It is a centrally acting muscle relaxant with an unclear mechanism of action. It is used as an adjunct treatment for symptoms of musculoskeletal disorders associated with painful muscle spasms. (Excerpt from Martindale Pharmacopoeia, 30th edition, p. 1206)
See also: Aspirin; Methopamoate (ingredients).
Drug Indications
In the United States, methopamoate tablets and injections are used as adjuncts to rest, physical therapy, and other measures to relieve discomfort caused by acute painful musculoskeletal disorders. In the United States, the upper limit of oral mesotherapy is 1500 mg four times daily for 2-3 days. In Canada, oral formulations containing methoxycabamor are available without a prescription for the treatment of pain caused by muscle spasms. However, if these combination formulations contain codeine, they must be purchased with a prescription.
FDA Label

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Mechanism of Action
The mechanism of action of methoxycabamor is believed to rely on its inhibitory effect on the central nervous system. This effect may be achieved by blocking spinal polysynaptic reflexes, reducing neurotransmission in the spinal cord and its polysynaptic pathways, and prolonging the refractory period of muscle cells. Studies have found that methoxycabamor has no effect on the contraction of muscle fibers, motor endplates, or nerve fibers.
The exact mechanism of action has not been determined. These drugs act on the central nervous system (CNS), rather than directly on skeletal muscle. Some of these drugs have been shown to preferentially inhibit polysynaptic reflexes. The muscle relaxant effect of most of these drugs is likely related to their central nervous system inhibitory (sedative) effect. /Skeletal Muscle Relaxants/

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Therapeutic Uses
Central Muscle Relaxants
Skeletal muscle relaxants are indicated as adjunctive therapy to other treatments, such as rest and physical therapy, to relieve muscle spasms caused by acute painful musculoskeletal disorders. /Included in US Product Labels/
Methoxycarbamovir is also FDA approved for the control of neuromuscular symptoms of tetanus. However, in the treatment of tetanus, it has been superseded by diazepam, or in severe cases by neuromuscular blocking agents such as pancuronium bromide. This therapy may be used as an adjunct to other measures such as debridement, tetanus antitoxin, penicillin, tracheotomy, fluid and electrolyte replacement, and supportive care.
Veterinarian: In dogs, cats, and horses, methoxycarbamovir is indicated for the treatment of acute inflammatory and traumatic skeletal muscle disorders and for the relief of muscle spasms.
For more complete data on the therapeutic uses of methoxycarbamovir (6 types), please visit the HSDB record page.
Drug Warnings
The most common adverse reactions to methoxycabamovir are drowsiness, dizziness, and lightheadedness. Blurred vision, headache, fever, and nausea may occur after oral, intramuscular, or intravenous administration. Anorexia has been reported after oral administration. One patient experienced nonmotorized intestinal obstruction after taking 10 grams of methoxycabamovir orally. Patients receiving this drug via intramuscular or intravenous administration have experienced adverse reactions such as metallic taste, gastrointestinal upset, nystagmus, diplopia, flushing, vertigo, mild muscle incoordination, syncope, hypotension, and bradycardia.
Patients receiving methoxycabamovir may experience allergic reactions such as urticaria, itching, rash, skin eruption, and conjunctivitis with nasal congestion. Anaphylactic shock has occurred after intramuscular or intravenous administration of this drug. While most patients with methoxycabamovir-induced syncope recover with supportive care, adrenaline, corticosteroids, and/or antihistamines have been used to improve recovery in some patients.
When administered intravenously, extravasation of methoxycabamor may cause thrombophlebitis, necrosis, and pain at the injection site. Intramuscular injection may also cause local irritation. Intravenous administration of methoxycabamor may cause minor hemolysis and increase the number of hemoglobin and red blood cells in the urine. Leukopenia may occur in rare cases.
Parenteral administration of this preparation should be used with caution in patients with epilepsy.
For more complete data on drug warnings for methoxycabamor (14 in total), please visit the HSDB record page.

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Pharmacodynamics
Methoxycabamor is a skeletal muscle relaxant, and its mechanism of action is not fully understood. Studies have shown that methoxycabamor can block spinal polysynaptic reflexes, reduce nerve conduction in the spinal cord and supraspinous polysynaptic pathways, and prolong the refractory period of muscle cells. Injection of methoxycabamor does not provide local anesthesia. Animal studies have shown that methoxycabamor can also prevent seizures following electric shock.

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1. Chemical classification and clinical application: Methopamo is a centrally acting skeletal muscle relaxant, chemically classified as a carbamate derivative. It has been clinically approved for the relief of acute musculoskeletal spasms (e.g., caused by injury or inflammation)[3]
.
2. Mechanism of action: Methopamo exerts its muscle relaxant effect by blocking the Na_v1.4 sodium channel in skeletal muscle, thereby reducing sodium ion influx, inhibiting myofibrillary depolarization, and thus reducing excessive muscle contraction[3]
.
3. Pharmacokinetic considerations in patients with renal impairment: Due to the prolonged half-life and reduced clearance in patients with severe renal impairment, dose adjustment (e.g., 50% of the standard dose) is recommended to avoid drug accumulation[2]
.
4. Metabolic characteristics: The main metabolic pathway (glucuronidation) is independent of cytochrome P450 enzymes, suggesting a low risk of drug interactions through P450-mediated metabolism[1]
.

C11H15NO5

241.24

241.095

532-03-6

Methocarbamol-d5;1189699-70-4;Methocarbamol-d3;1346600-86-9;Methocarbamol-13C,d3;2747917-88-8

4107

White to off-white solid powder

1.3±0.1 g/cm3

472.5±40.0 °C at 760 mmHg

95-97ºC

239.6±27.3 °C

0.0±1.2 mmHg at 25°C

1.541

0.55

2

5

7

17

236

0

GNXFOGHNGIVQEH-UHFFFAOYSA-N

InChI=1S/C11H15NO5/c1-15-9-4-2-3-5-10(9)16-6-8(13)7-17-11(12)14/h2-5,8,13H,6-7H2,1H3,(H2,12,14)

[2-hydroxy-3-(2-methoxyphenoxy)propyl] carbamate

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)

Solubility in Formulation 1: ≥ 3.5 mg/mL (14.51 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 35.0 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: ≥ 3.5 mg/mL (14.51 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 35.0 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: ≥ 3.5 mg/mL (14.51 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 35.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: 25 mg/mL (103.63 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication (<60°C).

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