Glutathione

Glutathione (gamma-L-glutamyl-L-cysteinyl-glycine) is a tripeptide of glutamate, cysteine and glycine and the main intracellular thiol antioxidant. It is a bulk substance with no FDA-approved drug product in the United States, and no FDA-labeled indication or dose exists. Oral glutathione is sold as a dietary supplement. Compounded preparations include injectable solutions for intramuscular or intravenous use and rectal or vaginal suppositories.

• No FDA-labeled indication exists. Prescribers use compounded glutathione at their discretion. Injectable glutathione is not FDA-approved for skin lightening and should not be used for that purpose.

Reduced glutathione (GSH) donates electrons through its cysteine thiol to neutralize reactive oxygen species and is oxidized to glutathione disulfide (GSSG), which glutathione reductase recycles using NADPH. GSH is a cofactor for glutathione peroxidases, conjugates electrophiles and drug metabolites through glutathione S-transferases, helps regenerate vitamins C and E, and maintains protein thiol status.

Exogenous glutathione is cleared rapidly. After intravenous administration, plasma glutathione falls within minutes, with a reported half-life of roughly 10 minutes, as it is hydrolyzed by gamma-glutamyl transpeptidase, mainly in the kidney, into its amino acids, which cells take up to resynthesize glutathione.

Oral bioavailability is low and variable because of intestinal and hepatic breakdown. Absorption after intramuscular, rectal or vaginal administration has not been well characterized; the rectal route only partly avoids first-pass metabolism.

• Known hypersensitivity to glutathione or any ingredient of the preparation.

• Hypersensitivity reactions, including rash, urticaria and, rarely, anaphylaxis. Injectable use should be supervised by a healthcare professional able to manage allergic reactions.
• Nebulized glutathione has caused bronchoconstriction in people with asthma; use caution in patients with reactive airway disease.
• Compounded injectables carry risks of contamination and endotoxin; preparations must meet USP <797> standards. Safety of long-term or high-dose use has not been established, and data in hepatic or renal impairment are limited.

• No clinically significant drug interactions have been well established. Because glutathione is an antioxidant, there is a theoretical concern that it could interfere with chemotherapy or radiation that relies on oxidative mechanisms; coordinate with the oncology team. Acetaminophen overdose depletes hepatic glutathione; the standard antidote is acetylcysteine, not glutathione.

Reported effects include injection-site pain, redness and swelling, flushing, nausea, abdominal cramping, bloating and loose stools, rash and, rarely, anaphylaxis. Rectal or vaginal use can cause local irritation, itching or burning. Isolated reports of liver test abnormalities after intravenous use have been described.

Glutathione is an endogenous compound, but the safety of supplemental glutathione in pregnancy and lactation has not been established. Use is not recommended during pregnancy or breastfeeding unless the prescriber judges the benefit to outweigh unknown risks.

Monitor for hypersensitivity reactions during and after injection, injection-site reactions, respiratory symptoms in patients with asthma, and local tolerance with suppositories. Consider periodic liver function testing with repeated intravenous use.

• Natural Medicines Comprehensive Database: Glutathione.
• USP General Chapter <797> Pharmaceutical Compounding, Sterile Preparations.
• USP General Chapter <795> Pharmaceutical Compounding, Nonsterile Preparations.