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Eur Respir J 2006; 27:865-866
Copyright ©ERS Journals Ltd 2006

The sulphoxidation of S-carboxymethyl-L-cysteine in COPD

G. B. Steventon1 and S. C. Mitchell2

1 Kings College London, Pharmaceutical Sciences Research Division, School of Biomedical and Health Sciences, and 2 Imperial College London, Section of Biological Chemistry, Division of Biomedical Sciences, Faculty of Natural Sciences, London, UK.

To the Editors:

Mucolytics, such as S-carboxymethyl-L-cysteine, have a role to play as an adjunct in the treatment of chronic obstructive airway disease, but their apparent unreliability has led to divided opinion concerning their usefulness 1–3. The failure to achieve any measurable benefit with some patients presumably reflects underlying interindividual differences within the patient cohort, and not that the drug itself is without efficacy. In this respect, one major topic affecting clinical efficacy of a drug is its disposition and fate following administration, and, in particular, those factors that influence its subsequent metabolism and deactivation.

The metabolic fate of S-carboxymethyl-L-cysteine, an extensively used and widely available mucoactive drug, is now known to be complex. Detailed and rigorous studies in humans have revealed that the biotransformation of the drug varies widely within the same individual, with little sulphoxide (sulphur oxygenated) metabolites being produced following night-time administration 4. This seemingly trivial observation is crucial, as recent work indicates that this drug functions as a free radical scavenger 5, 6 and that, in this respect, the sulphide (parent compound) is the active species with the sulphoxide metabolites (already oxidised) being inactive. Thus, a night-time intake of the drug should be more beneficial to the patient than daytime administration. However, this diurnal variation in metabolism (deactivation) is overlaid on an underlying genetic polymorphism that gives the patient population a spread of S-carboxymethyl-L-cysteine sulphoxidation capacities 7 (fig. 1Go). Those individuals who are relatively efficient sulphur oxidisers will rapidly produce inactive oxygenated metabolites, whereas those who have a relative deficiency in this process will be exposed to the active sulphide for a longer period of time, effectively mimicking the night-time dosing situation. In efficient sulphoxidisers, the standard dose of the drug may well have little effect. The underlying enzymology of these reactions is not yet clear, but two cytosolic enzymes, cysteine dioxygenase and phenylalanine 4-hydroxylase, have been implicated 8.


Figure 1
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  		Fig. 1— Distribution of S-Carboxymethyl-L-cysteine sulphoxidation capacities for 401 subjects (09.00Hr S-Carboxymethyl-L-cysteine 750mg p.o. 0–8Hr urine collection) expressed as a sulphoxidation index (SI; ratio sulphides/sulphoxides). The population can be divided into three sub-groups as follows. #: extensive metaboliser phenotype, 65.8% population (SI<6); : intermediate metaboliser phenotype, 31.7% (SI 6–80); +: poor metaboliser phenotype, 2.5% (SI>80).

 
It is evident that a "broad brush stroke" approach to therapy with this particular mucolytic agent will not work for everyone. The recognition that the same dose of S-carboxymethyl-L-cysteine will not be equally effective for all patients should enable this part of the therapeutic regimen to be tailored to each individual patient, or subgroup, of patients. Removing or withholding treatment because it appears ineffective in some subjects is manifestly incorrect for that proportion of the patient population for whom benefit may be gained. Some form of practical screening prior to mucolytic therapy would permit the correct dosage to be assigned.

We would welcome correspondence concerning the efficacy, or otherwise, of S-carboxymethyl-L-cysteine in the treatment of chronic obstructive pulmonary disease.

REFERENCES

  1. Asti C, Melillo G, Caselli GF, et al. Effectiveness of carbocysteine lysine salt monohydrate on models of airway inflammation and hyperresponsiveness. Pharmacol Res 1995;31:387–392.[CrossRef][Medline] [Order article via Infotrieve]
  2. Chalumeau M, Cheron G, Assathiany R, et al. Mucolytic agents for acute respiratory tract infections in infants: a pharmacoepidemiologic problem? Arch Pediatr 2002;9:1128–1136.[Medline] [Order article via Infotrieve]
  3. Carpagnano GE, Resta O, Foschino-Barbaro MP, et al. Exhaled interleukine-6 and 8-isoprostane in chronic obstructive pulmonary disease: effect of carbocysteine lysine salt monohydrate (SCMC-Lys). Eur J Pharmacol 2004;505:169–175.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  4. Steventon GB. Diurnal variation in the metabolism of S-carboxymethyl-L-cysteine in man. Drug Metab Dispos 1999;27:1092–1097.[Abstract/Free Full Text]
  5. Pinamonti S, Venturoli L, Leis M, et al. Antioxidant activity of carbocysteine lysine salt monohydrate. Panminerva Med 2001;43:215–220.[Medline] [Order article via Infotrieve]
  6. Brandolini L, Allegretti M, Berdini V, et al. Carbocysteine lysine salt monohydrate (SCMC-LYS) is a selective scavenger of reactive oxygen intermediates (ROIs). Eur Cytokine Net 2003;14:20–26.[Medline] [Order article via Infotrieve]
  7. Mitchell SC, Waring RH, Haley CS, Idle JR, Smith RL. Genetic aspects of the polymodally distributed sulphoxidation of S-carboxymethyl-L-cysteine in man. Brit J Clin Pharmacol 1984;18:507–521.[Medline] [Order article via Infotrieve]
  8. Goreish AH, Bednar S, Jones H, Mitchell SC, Steventon GB. Phenylalanine 4-monooxygenase and the S-oxidation of S-carboxymethyl-L-cysteine. Drug Metab Drug Interact 2004;20:159–174.[Medline] [Order article via Infotrieve]




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