Efficacy of S-carboxymethyl-L-cysteine for otitis media with effusion.

Dear Editor:

The frequent observation that some patients with otitis media with effusion benefit from treatment with S-carboxymethyl-L-cysteine (SCMC) implies that this drug is not without therapeutic efficacy. However, confusion and controversy arise over the usefulness of this mucolytic agent as some patients do not display any improvement following SCMC treatment. (1)

The reason for the different outcomes may have to do with factors that affect the pharmacokinetic profile of SCMC following its administration, especially its subsequent metabolism and deactivation. This has interested researchers for some time, since the metabolism of SCMC is under both genetic and diurnal control. (2,3) The enzyme responsible for the S-oxidation of SCMC to SCMC sulfoxide has been reported to be phenylalanine hydroxylase. (4,5) It has also been suggested that cysteine dioxygenase is involved in this biotransformation reaction, but to date no experimental evidence to support this hypothesis has been published.

The major route of SCMC metabolism is sulfoxidation, which results in a number of sulfoxide metabolites being found in the urine of patients who take SCMC. (Analysis of SCMC-related sulfides and sulfoxides in urine can be readily undertaken in any bioanalysis research laboratory. (2,3)) The genetic polymorphism in SCMC sulfoxidation results in the subdivision of the population into three cohorts with respect to their ability to sulfoxidize the sulfur moiety of the drug (figure). In a study of 401 patients by Mitchell et al, most patients (65.8%) were extensive metabolizers (EM phenotype), 31.7% were intermediate metabolizers (IM phenotype), and 2.5% were poor metabolizers (PM phenotype). (2) The PM phenotype actually produced no urinary sulfoxide metabolites.

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With respect to diurnal control, the involved enzymes are downregulated during the night. As a result, the production of sulfoxide metabolites is reduced (by 54.7% [+ or -] 15.6]). (6)

These seemingly insignificant observations are actually vital because recent work indicates that SCMC functions as a free radical scavenger (7) and that, in this respect, the sulfide (parent compound) is the active species and the sulfoxide metabolites (already oxidized) are inactive. Thus, administration of SCMC will benefit an individual with a PM or IM phenotype more than it will a patient with an EM phenotype. Moreover, in a patient with an EM phenotype, nighttime intake of the drug should be more beneficial than daytime administration.

Both the genetic and diurnal regulation of the sulfoxidation of SCMC have a dramatic effect on the therapeutic concentration of the drug in various patients. Therefore, it may be that the variability of pharmacodynamic responses to SCMC therapy is attributable to these two pharmacokinetic effects.

References

(1.) Pignataro O, Pignataro LD, Gallus G, et al. Otitis media with effusion and S-carboxymethylcysteine and/or its lysine salt: A critical overview. Int J Pediatr Otorhinolaryngol 1996;35:231-41.

(2.) Mitchell SC, Waring RH, Haley CS, et al. Genetic aspects of the polymodally distributed sulphoxidation of S-carboxymethyl-L-cysteine in mall. Br J Clin Pharmacol 1984:18:507-21.

(3.) Steventon GB. Diurnal variation in the metabolism of S-carboxymethyl-L-cysteine in humans. Drug Metab Dispos 1999;27: 1092-7.

(4.) Boonyapiwat B, Forbes B, Steventon GB. Phenylalanine hydroxylase: Possible involvement in the S-oxidation of S-carboxymethyl-l-cysteine. Anal Biochem 2004;335:91-7.

(5.) Goreish AH, Bednar S, Jones H, et al. Phenylalanine 4-monooxygenase and the S-oxidation of S-carboxymethyl-L-cysteine. Drug Metabol Drug Interact 2004;20:159-74.

(6.) Mitchell SC, Waring RH. The deficiency of sulfoxidation of S-carboxymethyl-L-cysteine. Pharmacol Ther 1989;43:237-49.

(7.) 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 Netw 2003; 14:20-6.

G.B. Steventon, BSe (Hons), PhD

Pharmaceutical Sciences Research Division

School of Biomedical and Health Sciences

King's College

London

S.C. Mitchell, BSc (Hons), PhD, DSc

Section of Biological Chemistry

Division of Biomedical Sciences

Faculty of Life Sciences

Imperial College

London