Pharmacology and Clinical Efficacy of Erdosteine in Chronic Obstructive Pulmonary Disease

Maurizio Moretti

Disclosures

Expert Rev Resp Med. 2007;1(3):307-316. 

In This Article

Introduction to Erdosteine

Erdosteine is manufactured by Edmond Pharma (Milan, Italy) and commercialized in 42 countries in Europe and worldwide under different trade names (e.g., Erdotin®, Erdomed® and Mucotec®). The drug was introduced as a mucolytic agent for chronic pulmonary diseases more than 10 years ago. Its effect is based on the breaking of the disulfide bridges of mucus glycoproteins, resulting in reduced sputum physical properties in patients with acute and chronic mucus hypersecretion.[10] Guidelines recommend its use to increase cough clearance[11] and the drug is prescribed widely for this purpose in many European and extra-European countries. However, the favorable effects of erdosteine extend much further than modulation of mucus viscosity and increase of tracheobronchial clearance; experimental and clinical studies evidenced four major pharmacological activities: antioxidant, anti-inflammatory, antibacterial and mucolytic activity.

The chemical name of erdosteine is N-(carboxymethylthioacetyl) homocysteine thiolactone, which has the appearance, as raw material, of a white microcrystalline powder with a mild characteristic smell. The erdosteine molecule (Figure 1) is characterized by the presence of two sulfur atoms, one in the aliphatic side chain and the second enclosed in the heterocyclic ring (thiolactone). With these two blocked thiol groups, erdosteine is an inactive prodrug.

Erdosteine and its metabolite I.

Erdosteine is stable only in the dry state or in acidic media. Following oral administration, erdosteine is stable in the stomach. When passing to a more alkaline environment, the thiolactone ring slowly opens, achieving, in the bloodstream, the complete transformation to metabolite I, N-thiodiglycolylhomocysteine, which is the active metabolite of erdosteine owing to this free thiol group (Figure 1).

Erdosteine, administered in single doses to normal adult volunteers, exhibits linear kinetics from 150 to 1200 mg. Plasma concentrations of the active metabolite I are approximately fivefold higher than those of erdosteine. After multiple doses (300-mg three-times daily for 8 days), the pharmacokinetics of erdosteine and metabolite I were comparable to a single administration of 900 mg, indicating no accumulation or metabolic activation after repeated dosing. Erdosteine is mainly excreted in the urine as an inorganic sulfate.[12]

Detectable levels of metabolite I can be found after 10 h, indicating a prolonged serum availability of the free thiol group and supporting twice-daily administration. No other metabolite was detected. In particular, the plasma concentration of homocysteine, considered a potential end product of erdosteine metabolism, was unchanged after repeated dosing.[13] Relevant to its pharmacological activity, both erdosteine and metabolite I were found in bronchial secretions in patients treated with erdosteine 300 mg twice daily for 1 week, with a significant increase of glutathione levels.[14]

The free SH group in metabolite I results in multiple pharmacological acivities, namely:

  • Mucolytic activity

  • Antibacterial activity

  • Antioxidant activity

  • Anti-inflammatory activity

These pharmacological activities were tested both in preclinical investigations in animal and in vitro models, and in human clinical trials.

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