Absorption, Distribution and Excretion
The bioavailability of oral ethambutol is approximately 75-80%. After oral administration of 25 mg/kg ethambutol, the peak plasma concentration (Cmax) is 2-5 µg/mL, and the time to peak concentration (Tmax) is 2-4 hours. In another study, the AUC0-8 value of ethambutol varied between 6.3 ± 5.5 hmg/L and 10.8 ± 7.6 hmg/L depending on CYP1A2 gene polymorphism. 50% of ethambutol is excreted in the urine as the unmetabolized parent compound, and 8-15% is excreted as inactive metabolites. 20-22% of the dose is excreted unchanged in the feces. The estimated volume of distribution of ethambutol in patients with tuberculosis and HIV infection is 76.2 L. The estimated oral clearance of ethambutol in patients with tuberculosis and HIV infection is 77.4 L/h.
Approximately 75-80% of oral ethambutol hydrochloride is rapidly absorbed from the gastrointestinal tract. Co-administration with food has no significant effect on drug absorption. Following a single oral dose of 25 mg/kg ethambutol hydrochloride, peak serum ethambutol concentrations can reach 2-5 μg/mL within 2-4 hours. Serum drug concentrations are undetectable 24 hours after administration.
In patients with normal renal function, no drug accumulation was observed with a once-daily dose of 25 mg/kg ethambutol. In patients with impaired renal function, higher serum drug concentrations may lead to accumulation.
Ethambutol is widely distributed in most body tissues and fluids. The highest drug concentrations are found in erythrocytes, kidneys, lungs, and saliva; lower concentrations are found in ascites, pleural fluid, brain, and cerebrospinal fluid. Following a single oral dose, the peak concentration of ethambutol in erythrocytes is approximately twice the peak plasma concentration, and this ratio is maintained for at least 24 hours. In patients with meningitis, oral administration of ethambutol hydrochloride 25 mg/kg resulted in peak cerebrospinal fluid concentrations of 0.15–2.0 ug/mL. Ethambutol does not penetrate intact meninges, but 10% to 50% of ethambutol may penetrate the meninges in patients with tuberculous meningitis. The volume of distribution is 1.6 L/kg. For more complete data on the absorption, distribution, and excretion of ethambutol (9 items in total), please visit the HSDB record page. Metabolites/Metabolites: Ethambutol is primarily oxidized by aldehyde dehydrogenase to aldehyde metabolites, which are then converted to dicarboxylic acid 2,2'-(ethylenediimino)dibutyric acid. Up to 15% of ethambutol is excreted as two metabolites: an aldehyde and a dicarboxylic acid derivative.
Ethambutol is partially inactivated in the liver, oxidized to the aldehyde intermediate 2,2'-(ethylenediimino)dibutanal, which is then converted to the decarboxylation derivative 2,2'-(ethylenediimino)dibutyric acid.

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Biological Half-Life
In patients with normal renal function, the half-life of ethambutol is 3.3 hours. In patients with renal failure, the half-life may be 7 hours or longer.
In patients with normal renal function, the plasma half-life of ethambutol is approximately 3.3 hours. In patients with impaired renal or hepatic function, the half-life is prolonged. In patients with renal failure, the half-life may be 7 hours or longer.
Six healthy adult volunteers received a constant-rate infusion of 15 mg/kg ethambutol (EMB) over 1 hour. Plasma and urine samples were collected at 24 and 72 hours post-infusion. …EMB levels showed a multiphasic decay after infusion. EMB levels exhibited a biexponential decay within 12 hours post-infusion. However, plasma concentrations at 24 hours were higher in all subjects than predicted using a two-compartment model. The mean α-phase half-life for these subjects was 8.6 minutes, and the β-phase half-life ranged from 2.5 to 3.6 hours (mean 3.1 hours). The mean γ-phase half-life was estimated from 12 to 24 hours of plasma data to be 1.2 ± 3.6 hours. The terminal γ-phase half-life was calculated from 12 to 72 hours of urinary data to be 15.4 ± 1.7 hours. … Plasma EMB clearance ranged from 7.47 to 8.87 mL/min/kg (mean 8.57 mL/min/kg). …

Toxicity Summary
Identification: Ethambutol is used to treat tuberculosis. Ethambutol is an odorless, crystalline, hygroscopic powder. It is soluble in water, ethanol, chloroform, and methanol, and slightly soluble in ether. Human Exposure: Overview: Major Risks and Target Organs: Prolonged use of ethambutol may cause visual and neurological disturbances, allergic reactions, gastrointestinal symptoms, psychiatric symptoms, and transient hepatic impairment. The incidence of hepatic impairment is extremely low. Elevated serum uric acid levels and acute gouty arthritis have been reported. Clinical Effects Overview: Acute overdose may cause gastrointestinal symptoms, hallucinations, and optic neuritis. Symptoms of acute overdose include nausea, abdominal pain, fever, confusion, visual hallucinations, and optic neuropathy (retrobulbar optic neuritis), which can occur at doses exceeding 10 grams. The consequences of ethambutol overdose are not fully understood. The following have been reported during prolonged ethambutol use: Visual Disorders: Ethambutol may cause decreased vision, which appears to be caused by optic neuritis. Central scotoma and red-green color blindness may also occur. Allergic reactions: rash, allergic-like reactions, dermatitis, and itching. Gastrointestinal symptoms: abdominal pain, anorexia, nausea, and vomiting. Neurological and psychiatric symptoms: headache, peripheral neuritis, dizziness, confusion, disorientation, and hallucinations. Other side effects: jaundice, transient hepatic impairment, fever, elevated serum uric acid levels, arthralgia, acute gouty arthritis, and malaise. Ethambutol may diffuse into breast milk. Ethambutol is a synthetic oral antibiotic, a derivative of ethylenediamine. Contraindications: Contraindicated in patients with known hypersensitivity to ethambutol hydrochloride. Renal insufficiency, advanced age, and optic neuritis are relative contraindications. Route of administration: Oral: Ethambutol is for oral administration only. Absorption: Approximately 80% of orally administered ethambutol is absorbed through the gastrointestinal tract, with the remainder excreted unchanged in feces. Food has no significant effect on absorption. Distribution: Ethambutol readily diffuses into red blood cells and may enter the cerebrospinal fluid in cases of meningitis. At steady state, the concentration in erythrocytes is approximately twice that in plasma. Ethambutol has been reported to cross the placenta and be secreted into breast milk. Biological half-life (by route of exposure): The serum half-life at therapeutic doses is 3 hours, which is prolonged in renal failure as 80% of the drug is excreted via the kidneys. Metabolism: The primary metabolic pathway appears to be the initial oxidation of the alcohol to an aldehyde intermediate, followed by conversion to a dicarboxylic acid. Elimination (by route of exposure): Within 24 hours of oral ethambutol administration, approximately 50% of the initial dose is excreted unchanged in the urine, with an additional 8% to 15% excreted as metabolites. 20% to 22% of the initial dose is excreted unchanged in the feces. Mechanism of action: Toxicokinetics: The underlying cause of visual alterations appears to be metabolic disturbances resulting from the depletion of copper and zinc, which are cofactors for many enzymes. The eyes typically contain significant amounts of zinc. Most zinc is found in the pigment cells of the outer retina, where it functions as a metal cofactor for retinol (alcohol) dehydrogenase. Pharmacodynamics: Ethambutol is an oral chemotherapy drug with specific efficacy against actively growing mycobacterial microorganisms, including Mycobacterium tuberculosis. Ethambutol has antibacterial activity, appearing to inhibit the synthesis of one or more metabolites, leading to impaired cellular metabolism, cessation of proliferation, and cell death. No cross-resistance with other existing antimycobacterial drugs has been found. Ethambutol has been shown to be effective against Mycobacterium tuberculosis strains, but appears ineffective against fungi, viruses, or other bacteria. Ethambutol is also effective against some atypical mycobacteria, including Mycobacterium Kansas. Primary resistance to ethambutol is uncommon in developed countries, but resistant Mycobacterium tuberculosis strains can easily develop if the drug is used alone. Human Data: Adults: A relatively higher incidence of subclinical color vision impairment has been reported in patients receiving daily ethambutol as part of anti-tuberculosis chemotherapy compared to 50 patients receiving other anti-tuberculosis drugs. Peripheral neuropathy has been reported in tuberculosis patients receiving ethambutol and other drugs. Drug Interactions: A crossover study involving 13 patients with tuberculosis indicated that concomitant administration of aluminum hydroxide may delay and reduce the absorption of ethambutol in some patients. Adverse effects may be enhanced when ethambutol is used in combination with isoniazid or rifampin. Major Adverse Effects: Ethambutol may cause decreased vision, which appears to be caused by optic neuritis and is related to dose and duration of treatment. These effects are usually reversible if the drug is discontinued in time. Ethambutol may cause narrowing of the visual field, central and peripheral scotomas, and red-green color blindness, the latter of which may be related to retrobulbar optic neuritis. Approximately 50% of patients treated with ethambutol may have reduced uric acid renal clearance, and ethambutol can induce acute gout in patients with gout or impaired renal function. Cholestatic jaundice has been reported. Animal/Plant Studies: Relevant Animal Data: Long-term high-dose ethambutol toxicology studies in dogs showed myocardial injury and failure, as well as depigmentation of the ocular reflective layer, but the significance of these effects is unclear. Central nervous system degenerative changes have also been observed in dogs on long-term ethambutol hydrochloride administration, but these changes appear to be dose-independent. In rhesus monkeys, neurological symptoms appeared after months of daily administration of high doses of ethambutol. These results were associated with specific serum ethambutol hydrochloride levels and well-defined neuroanatomical changes in the central nervous system. Focal interstitial myocarditis also occurred in monkeys on long-term administration of high doses of ethambutol hydrochloride. Drug Interactions: Patients taking ethambutol (20-25 mg/kg/day) concurrently with oral digoxin (0.1 mg/day) had significantly lower serum digoxin levels than the control group (16.6 ng/mL vs. 35 ng/mL). Blood proteins bound to digoxin were similar in both groups. Its metabolism may be accelerated. Concomitant use of ethambutol with other neurotoxic drugs may increase the risk of neurotoxicity, such as optic neuritis and peripheral neuritis. Aluminum salts may delay and reduce the absorption of ethambutol. This study evaluated the effects of repeated rifabutin administration on the pharmacokinetics and metabolism of ethambutol in ten healthy volunteers. Subjects received a single oral dose of 1200 mg ethambutol on days 1 and 10, followed by single oral doses of 300 mg rifabutin daily from days 3 to 9. Results showed no statistically significant differences in plasma pharmacokinetic parameters (Cmax, tmax, AUC, half-life, and MRT) and renal clearance, but a significant decrease in urinary excretion of unchanged ethambutol. The observed decrease in urinary ethambutol excretion may be due to individual variability in reported urinary ethambutol excretion. However, a slight induction or activation of renal alcohol and/or aldehyde dehydrogenase isoenzymes by rifabutin cannot be ruled out, and this effect may not be clinically significant. Evidence of rifabutin self-induction in metabolism was present in this study; this is evidenced by the lower plasma concentration obtained 24 hours after the seventh dose compared to the theoretical concentration.

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Non-human toxicity values
Oral LD50 in mice: 2800 mg/kg / when mixed with isoniazid methanesulfonate/
Intraperitoneal LD50 in mice: 2210 mg/kg / when mixed with isoniazid methanesulfonate/

Safi H, Lingaraju S, Amin A, Kim S, Jones M, Holmes M, McNeil M, Peterson SN, Chatterjee D, Fleischmann R, Alland D. Evolution of high-level ethambutol-resistant tuberculosis through interacting mutations in decaprenylphosphoryl-β-D-arabinose biosynthetic and utilization pathway genes. Nat Genet. 2013 Oct;45(10):1190-7. doi: 10.1038/ng.2743. Epub 2013 Sep 1. PubMed PMID: 23995136.

Therapeutic Uses

Anti-tuberculosis Drugs
Ethambutol, used in combination with other anti-tuberculosis drugs, is indicated for the treatment of various types of tuberculosis caused by Mycobacterium tuberculosis, including tuberculous meningitis. /Included on US product label/
Ethambutol is also used to treat atypical mycobacterial infections, such as Mycobacterium avium complex (MAC) infections. /Not included on US product label/
Drug Warnings
No studies have been conducted on the relationship between the efficacy of ethambutol and age in children under 13 years of age. Ethambutol is generally not recommended for children (under 6 years of age) whose vision cannot be monitored.
However, ethambutol should be considered for all children who are resistant to other drugs and have proven or potential sensitivity to ethambutol.
The most common adverse reaction of ethambutol is optic neuritis, manifested as decreased vision, narrowed visual field, central and peripheral scotomas, and loss of red-green color vision. The degree of ocular toxicity appears to be related to the dose and duration of ethambutol treatment. However, there are reports of this toxicity even after only a few days of use, which may be a specific reaction. Other adverse reactions to ethambutol include dermatitis, itching, headache, malaise, dizziness, fever, confusion, disorientation, possible hallucinations, arthralgia, and rare anaphylactic reactions. In addition, ethambutol can occasionally cause gastrointestinal upset, abdominal pain, nausea, vomiting, and anorexia. Peripheral neuritis, with numbness and tingling in the extremities, has been reported occasionally but is not uncommon. Elevated serum uric acid levels and acute gout attacks have been occasionally observed in patients treated with ethambutol, possibly due to decreased renal clearance of uric acid. Abnormal liver function test results suggest possible transient liver impairment. At least one patient developed cholestatic jaundice after using ethambutol alone or in combination with streptomycin; this jaundice appears to be ethambutol-induced. Visual examination should be performed before starting ethambutol treatment and regularly during treatment. Patients taking more than 15 mg/kg daily should be examined monthly. The examination should include fundus examination, finger visual field testing, and color vision discrimination tests. Patients experiencing ocular adverse reactions during ethambutol treatment may experience subjective visual symptoms before or simultaneously with decreased vision. All patients taking this medication should be regularly questioned about the presence of blurred vision and other subjective visual symptoms, and should be advised to report any such changes to their doctor immediately. If significant changes in vision occur, ethambutol should be discontinued immediately.
For more complete data on ethambutol (10 in total), please visit the HSDB record page.

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Pharmacodynamics
Ethambutol is indicated for the treatment of pulmonary tuberculosis in combination with other anti-tuberculosis drugs. Due to daily administration, it has a long duration of action and a moderate therapeutic window. Patients should be informed of the risks of optic neuritis and hepatotoxicity.

C10H24N2O2

204.183

74-55-5

Ethambutol dihydrochloride;1070-11-7;Ethambutol-d4;1129526-19-7;Ethambutol-d10;1129526-24-4;Ethambutol-d8;1129526-23-3

14052

Crystals
WHITE, CRYSTALLINE POWDER

1.0±0.1 g/cm3

345.3±22.0 °C at 760 mmHg

199 - 204ºC

113.7±12.9 °C

0.0±1.7 mmHg at 25°C

1.478

-0.05

4

4

9

14

109

2

CC[C@H](NCCN[C@@H](CC)CO)CO

AEUTYOVWOVBAKS-YHMJZVADSA-N

InChI=1S/C10H24N2O2/c1-3-9(7-13)11-5-6-12-10(4-2)8-14/h9-14H,3-8H2,1-2H3/t9-,10?/m1/s1

1-Butanol, 2,2'-(1,2-ethanediyldiimino)bis-, (R)-

Etambutol Aethambutolum Diambutol Purderal Tibutol

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.)