REEVALUATION OF THE METABOLISM OF CARBOCISTEINE IN A BRITISH WHITE-POPULATION

It has been claimed that the amino acid derivative carbocisteine is pr edominantly metabolized by sulfoxidation and that this pathway exhibit s a genetic polymorphism. Moreover, those subjects with a 'poor metabo lizer' phenotype have been thought to have a genetic predisposition to developing certain diseases. We have confirmed the observations of ot hers that this marker drug does not undergo significant S-oxidation. F urthermore, a novel urinary metabolite, S-(carboxymethylthio)-L-cystei ne (CMTC) has recently been identified. To determine if a genetic poly morphism for this biotransformation pathway exists, metabolic ratios ( % urinary excretion carbocisteine/% urinary excretion CMTC) for 120 he althy volunteers were assessed using high-performance thin-layer chrom atography. Urinary excretion of the parent drug ranged from 6% of the dose administered to 56% (mean +/- SD, 23.4 +/- 0.8%). No cysteinyl su lfoxide metabolites were identified in the urine samples. The amount e xcreted as CMTC exhibited a 12-fold variation but only accounted for m ean of 4.4% (1-12%) of the dose given. Two individuals initially had h igh metabolic ratios (> 30), however, on rechallenge both their MRs we re less than 5. Therefore, carbocisteine is not an appropriate probe d rug for sulfoxidation. The formation of the novel metabolite CMTC appe ars to exhibit polymorphism, although the considerable intra-subject v ariation for its formation does not allow assignment of a phenotype.