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The mucoactive drug, S-carboxymethyl-L-cysteine (SCMC) is used therapeutically as an effective and safe treatment for the long-term management of COPD (chronic obstructive pulmonary disease) and OME (otitis media with effusions or “glue ear”) [1]. The exact mechanism of action is unknown but several hypotheses have been postulated [1].

Absorption In humans subjects, over 98% of the radioactivity was excreted in a 0–72 hour urine collection after oral ingestion of [35S]-SCMC. A lower value of 85% was recovered after [14C]-SCMC was administered orally. A large proportion of this radioactivity ([35S] 68%; [14C] 51%) was recovered during the first 0–6 hours. Virtually nothing (<0.5% dose) was found in the faeces [1]. Thus the bioavailability of SCMC in humans based on these balance studies was 0.98 (98%) for [35S]-SCMC and 0.85 (85%) for [14C]-SCMC [2].

Distribution Tissue distribution and autoradiographic studies in the mouse ([35S]-SCMC) and rat ([35S]-SCMC and [14C]-SCMC) have shown that the radioactivity is rapidly absorbed from the gastrointestinal tract. It appears in the blood and tissues within 2 minutes, reaching a plasma maximum at approximately 1–2 hours. Radioactivity could be detected in the cartilage, kidney, liver, lung, skin, spleen, and thymus, but neither in the brain nor the heart. A more recent study has reported extremely low, but detectable, SCMC levels in the mouse brain after intra-peritoneal administration [1]. The radiolabel appeared to have an affinity for the pancreas, where levels were higher than in the plasma. Amounts also continued to be concentrated within the lung, even when surrounding plasma levels were falling. In humans, pharmacokinetic data reported within the literature is almost non-existent The compound appears to be quickly absorbed from the gastrointestinal tract, reaching peak plasma concentrations at approximately 2 hours. The plasma half-life (t1/2) was of a similar order, indicating rapid removal of the parent compound, presumably through metabolism and excretion. The obtained kinetics conformed to a one-compartment open model in humans, although recent work with animals tentatively implied the possibility of a two-compartment model, especially using data obtained from later time points [1].

Metabolism SCMC undergoes extensive metabolism in humans with S-oxidation producing a variety of S-oxide metabolites (SCMC S-oxides, S-methyl-L-cysteine S-oxide, N-acetyl SCMC S-oxide, N-acetyl-S-methyl-L-cysteine S-oxide), decarboxylation (S-methyl-L-cysteine), N-acetylation (N-acetyl-SCMC, N-acetyl-S-methyl-L-cysteine), deamination-decarboxylation (thiodiglycolic acid) and glucuronidation (SCMC glucuronide) being reported [1,3].

Elimination The major route of elimination is via the urine with 98% of the radioactivity of [35S]-SCMC and 85% of the radioactivity of [14C]-SCMC recovered in the urine in 96 hours following oral administration. Less than 0.5% of the radioactivity was recovered in the faeces following oral administration of [35S or 14C]-SCMC [1,2,3]. Approximately 12% of the radioactivity after oral administration of [14C]-SCMC has been reported to be exhaled in the breath [2].

Regulation of metabolism The major route of metabolism in day light hours is S-oxidation and this is reported to be both genetic and hormonal control [1,3]. A pharmacogenetic polymorphism in the production of the S-oxide metabolites affects 2-3% of white Western Europeans (no studies have been undertaken in other ethnic groups) [1,3]. The enzyme response for this metabolic biotransformation is, phenylalanine hydroxylase (PAH) [1,4,5]. In addition the S-oxidation pathway is under circadian control with the S-oxidation pathway showing reduced metabolic capacity at night [1]. The path route of metabolism during night time is the deamination-decarboxylation pathway. Thus the timing of administration of SCMC can result in both quantitative and qualitative changes in metabolism [1]

References

[1] Mitchell, S.C., Steventon, G.B. (2012) S-Carboxymethyl-L-cysteine. Drug Metabolism Reviews, 44: 129–147.

[2] Waring, R.H., Mitchell, G.B. (1982) The metabolism and elimination of S-carboxymethyl-L-cysteine in man. Drug Metabolism and Dispositions, 10:61-62.

[3] Mitchell, S.C, Waring, R.H, Haley, C.S., Idle, J.R., Smith, R. L. (1984) Genetic aspects of the polymodally distributed sulphoxidation of S-carboxymethyl-L-cysteine in man. British Journal of Clinical Pharmacology, 18: 507-521.

[4] Boonyapiwat, B., Forbes, B., Mitchell, S., Steventon, G.B. (2008) Phenylalanine hydroxylase and the S-oxidation of S-carboxymethyl-L-cysteine by human cytosolic fractions. Drug Metabolism and Drug Interactions, 23: 261-282.

[5] Boonyapiwat, B., Panaretou, B., Forbes, B., Mitchell, S.C., Steventon, G.B. (2009) Human phenylalanine monooxygenase and thioether metabolism. Journal of Pharmacy and Pharmacology, 61: 63-67.