Introduction
Glutathione (γ-L-glutamyl-L-cysteinylglycine) is a ubiquitous tripeptide thiol present in virtually all mammalian cells, functioning as a critical endogenous antioxidant. While not FDA-approved as a pharmaceutical drug in the United States, it is utilized as a dietary supplement and is available as a prescription medication in some countries for specific indications. Glutathione plays essential roles in cellular protection, detoxification, and redox homeostasis.
Mechanism of Action
Glutathione exerts its effects through multiple mechanisms:
- Antioxidant activity: Directly scavenges reactive oxygen species (ROS) and free radicals
- Cofactor function: Serves as an essential cofactor for glutathione peroxidase and glutathione transferase enzymes
- Detoxification: Conjugates with xenobiotics and carcinogens via phase II metabolism
- Redox regulation: Maintains cellular thiol-disulfide balance through the glutathione disulfide (GSSG)/glutathione (GSH) redox couple
- Amino acid transport: Participates in the γ-glutamyl cycle for amino acid transport across cell membranes
Indications
FDA-approved indications: None in the United States Internationally approved/recognized uses:- Hepatoprotection in alcoholic liver disease, drug-induced hepatotoxicity, and viral hepatitis
- Adjuvant therapy in chemotherapy-induced toxicity
- Treatment of poisoning (particularly acetaminophen overdose in some regions)
- Idiopathic pulmonary fibrosis (in some countries)
- Antioxidant supplementation in various oxidative stress conditions
- Support in neurodegenerative disorders
- Adjunctive therapy in HIV/AIDS
- Skin lightening (topical and systemic)
Dosage and Administration
Oral administration: 250-1000 mg daily (limited bioavailability) Intravenous: 600-1800 mg daily (common in clinical settings) Inhalation: 600 mg twice daily (for pulmonary conditions) Topical: 2-5% formulations for dermatological use Special populations:- Renal impairment: Dose adjustment may be necessary
- Hepatic impairment: No specific recommendations
- Elderly: No specific dosage adjustment recommended
- Pediatrics: Safety and efficacy not established
Pharmacokinetics
Absorption: Poor oral bioavailability (<10%) due to hydrolysis by γ-glutamyl transpeptidase in the gastrointestinal tract Distribution: Widely distributed throughout tissues; highest concentrations in liver, kidney, spleen, and pancreas Metabolism: Hydrolyzed to constituent amino acids by γ-glutamyl transpeptidase and dipeptidases Elimination: Renal excretion of metabolites; half-life approximately 10 minutes in plasma Cellular uptake: Via specific transporters and enzymatic processingContraindications
- Known hypersensitivity to glutathione or its components
- History of severe allergic reactions to previous administration
Warnings and Precautions
- Anaphylaxis: Rare but serious hypersensitivity reactions reported
- Asthma exacerbation: Bronchoconstriction may occur with inhaled administration
- Electrolyte imbalance: May cause hypokalemia with high-dose IV administration
- Pregnancy: Category C (risk cannot be ruled out)
- Lactation: Safety not established
- Long-term safety: Limited data on chronic high-dose administration
Drug Interactions
- Acetaminophen: Glutathione may mitigate hepatotoxicity
- Chemotherapeutic agents: May reduce chemotherapy-induced side effects
- Cisplatin: Possible reduction in nephrotoxicity
- Antioxidants: Potential synergistic effects with other antioxidants
- Hepatotoxic drugs: May provide protective effects
Adverse Effects
Common:- Abdominal discomfort (oral administration)
- Mild rash or itching
- Transient nausea
- Unpleasant odor (with IV administration)
- Anaphylactic reactions
- Severe bronchospasm (inhaled route)
- Significant hypokalemia
- Stevens-Johnson syndrome (case reports)
Monitoring Parameters
- Efficacy monitoring: Disease-specific parameters (liver function tests, pulmonary function tests)
- Safety monitoring:
- Serum potassium levels (with high-dose IV) - Renal function - Signs of hypersensitivity - Respiratory status (with inhaled administration)
- Therapeutic drug monitoring: Not routinely performed
Patient Education
- Inform patients that glutathione is not FDA-approved as a drug in the US
- Discuss potential benefits and limitations based on available evidence
- Advise reporting any signs of allergic reaction immediately
- Explain proper administration techniques for prescribed formulations
- Caution against unproven claims regarding anti-aging or disease-curing properties
- Emphasize the importance of obtaining glutathione from reputable sources
- Discuss potential interactions with other medications and supplements
References
1. Pompella A, et al. The changing faces of glutathione, a cellular protagonist. Biochem Pharmacol. 2003;66(8):1499-1503. 2. Wu G, et al. Glutathione metabolism and its implications for health. J Nutr. 2004;134(3):489-492. 3. Richie JP Jr, et al. Randomized controlled trial of oral glutathione supplementation on body stores of glutathione. Eur J Nutr. 2015;54(2):251-263. 4. Fraternale A, et al. Glutathione and glutathione derivatives in immunotherapy. Biol Chem. 2017;398(2):261-275. 5. De Flora S, et al. Strategies for cancer chemoprevention: the role of glutathione. Eur J Cancer Prev. 1995;4(1):41-49. 6. Nuttall SL, et al. Glutathione: in sickness and in health. Lancet. 1998;351(9103):645-646. 7. Clinical management of poisoning: WHO guidelines. World Health Organization, 2018. 8. Japanese Pharmacopoeia, 17th Edition. Ministry of Health, Labour and Welfare, 2016.