Identification of the “major” polymorphic carbocysteine metabolite as [formula omitted]

Abstract

The metabolism of the mucolytic agent carbocysteine ( S- carboxymethyl- l-cysteine , CMC) has attracted substantial interest during recent years [1]. It has been reported that sulphoxidation of CMC and its cysteinyl metabolites consitutes a major pathway of biotransformation. Moreover, it has been suggested that CMC sulphoxidation exhibits a genetic polymorphism expressed in two phenotypes in the population, the poor sulphoxidizers (PS) and the extensive sulphoxidizers (ES) [2]. This sulphoxidation polymorphism has been linked to certain idiopathic diseases ( e.g. primary biliary cirrhosis) and the toxicity of sulphur-containing drugs ( e.g. d-penicillamine, sodium aurothiomalate) [1]. However, more detailed metabolic studies on CMC and a carbon-13 labelled analogue ( S- carboxy-[ 13 C] methyl- l-cysteine , 13C-CMC) have demonstrated the absence of significant amounts of any of the putative cysteinyl sulphoxide metabolites in the urine. These studies which were based on HPLC [3–5], 13C NMR [5,6], and gas chromatography/mass spectrometry (GC/MS) [7] demonstrated that, besides unchanged carbocysteine, thiodiglycolic acid (di-[carboxymethyl] sulphide, TDGA) and its sulphoxide (TDGA-SO) were the major biotransformation products of CMC in man [8]. Approximately 6–8 hr after administration of the drug, urinary excretion of an additional novel metabolite ( 1) was observed by TLC after sulphur-selective visualization [9]. This particular metabolite 1 of yet unknown structure was the only urinary component exhibiting polymorphic character present after oral administration of CMC [10]. About 7.5–10% of the two populations excreted only marginal amounts of 1, and a more than two-thousand fold difference in the urinary excretion of metabolite 1 has been estimated by TLC [10,11]. The objective of this study was to isolate and identify this metabolite.