Re-evaluation of the metabolism of carbocisteine in a British white population.
It has been claimed that the amino acid derivative carbocisteine is predominantly metabolized by sulfoxidation and that this pathway exhibits a genetic polymorphism. Moreover, those subjects with a 'poor metabolizer' phenotype have been thought to have a genetic predisposition to developing certain diseases. We have confirmed the observations of others that this marker drug does not undergo significant S-oxidation. Furthermore, a novel urinary metabolite, S-(carboxymethylthio)-L-cysteine (CMTC) has recently been identified. To determine if a genetic polymorphism for this biotransformation pathway exists, metabolic ratios (% urinary excretion carbocisteine/% urinary excretion CMTC) for 120 healthy volunteers were assessed using high-performance thin-layer chromatography. Urinary excretion of the parent drug ranged from 6% of the dose administered to 56% (mean +/- SD, 23.4 +/- 0.8%). No cysteinyl sulfoxide metabolites were identified in the urine samples. The amount excreted as CMTC exhibited a 12-fold variation but only accounted for mean of 4.4% (1-12%) of the dose given. Two individuals initially had high metabolic ratios (> 30), however, on rechallenge both their MRs were less than 5. Therefore, carbocisteine is not an appropriate probe drug for sulfoxidation. The formation of the novel metabolite CMTC appears to exhibit polymorphism, although the considerable intra-subject variation for its formation does not allow assignment of a phenotype.
Gregory
W L
WL
Department of Pharmacological Sciences, University of Newcastle upon Tyne, Medical School, UK.
James
O F
OF
Turner
I
I
Meese
C O
CO
Idle
J R
JR
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001711:Biotransformation; D002233:Carbocysteine / Q000031:analogs & derivatives / Q000378:metabolism* / Q000493:pharmacokinetics / Q000652:urine; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D011110:Polymorphism, Genetic; D006113:United Kingdom; D044465:White People / Q000235:genetics
C020249:S-carboxymethylthiocysteine; D002233:Carbocysteine