Direct determination of thioamide drugs in biological fluids by cathodic stripping voltammetry

Abstract

A method has been developed to determine several sulfur-contalnlng drugs in plasma and urine at concentrations down to 2 X IO-' M using cathodic stripping voltammetry at the hanging mercury drop electrode. Naturallyoccurrlng sulfur compounds such as glutathione, thiamlne, methionine, cystine, cysteine and H2S and anionic species such as chloride Ion are shown not to interfere. Results are shown to be accurate, with a precislon of 2.9% at the 5 X IO-' M level on 2-mL samples. An experimental procedure is described which Involves a 1:l dilution of the sample wlth Britton-Robinson buffer pH 4.78 followed by electroiysls at +O.O5V (vs. SCE) and subsequent cathodic strlpplng to -0.75V (vs. SCE). Standard addition Is used to determine the drug concentratlon. The effect of pH on protein preclpitatlon from biological samples has also been studied.This paper considers the application of cathodic stripping voltammetry to the direct determination of several sulfur containing drugs in body fluids at levels encountered following therapeutic administration, without the need for prior drug extraction.The analysis of drugs and their metabolites in body fluids is usually achieved by solvent extraction followed by the application of a suitable analytical technique such as gas chromatography ( I ) , high pressure liquid chromatography (2), fluorescence (3), polarography ( 4 , 5 ) , spectrophotometry (6), radioimmunoassay (7, 8) or mass fragmentography (9). Problems most commonly encountered include incomplete extraction and lack of analytical reproducibility. Any method which eliminates the necessity for extractions while maintaining specificity would greatly simplify and improve biological sample analysis, particularly if a good precision of 2-3 % was maintained.In the case of thioamide drugs, e.g., compounds I-VI (Figure l), the lability of the thioamide moiety makes their simple extraction difficult since degradation can occur to the corresponding amide or nitrile (10) during the extraction step with the production of elemental sulfur and hydrogen sulfide. In the study of the metabolism of these thioamides, rapid and direct analytical methods are required which can accurately measure drug concentrations of the order of lo-' to M. Such methods of course need to discriminate between the drug, its metabolites, and naturally-occurring sulfur compounds such as glutathione, methionine, cysteine, cystine, thiamine, and hydrogen sulfide.The use of anodic polarographic processes which involve mercury salt formation is well established for pharmaceutical analysis at concentration levels of M and the application of polarography for the analysis of ethionamide (compound 11) in blood and urine has been described using its polarographic reduction wave (11). These methods, however, lack Present address, Chemistry Institute, University of Aarhus, 8000 Aarhus C, Denmark. the sensitivity required for drug metabolism studies. Differential pulse polarography has found application in the determination of drugs in body fluids after solvent extracti...

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