Thiols metabolites

Fig. 7.11. Metabolism of S-(l- [(2,3,4,5-tetrahydro-2-oxothiophen-3-yl)amino]carbonyl ethyl) thiophene-2-carbothioate (MR 889, 7.71) in rats to the active thiol metabolite homocysteine thiolactone thiolactamide (7.72) and to thiophene-2-carboxylic acid (7.73) [154], Subsequent reactions of hydrolysis and conjugation are also shown.

Amifostine is hydrolyzed rapidly to 2-[(3-aminopropyl)amino]ethane-thiol (9.64) at the acidic pH of the stomach, and by alkaline phosphatases in various tissues. After intravenous administration to cancer patients, the plasma half-lives were found to be in the order of minutes. This is highly relevant, since most or all pharmacological effects of amifostine can be ascribed to its thiol metabolite. 

Determination of various analgesic and antipyretic pharmaceuticals on reversed phase has included not only the analysis of serum levels of aspirin, salicylic acid and salicyluric acid using acidified acetonitrile (557), or methanol (338), but also suUinpyrazone under isocratic conditions (339), and 6-chloro-a-methylcarbazole-2-acetic acid (340). The polar thiol metabolites of acetaminophen were analyzed by RPC and the method was found to be superior to other chromatographic techniques used in this analysis (341). 

Amifostine is a cytoprotective adjuvant used to reduce the incidence of neutropenia-related fever and infection induced by DNA-binding chemotherapeutic agents. It is an organic thiophosphate prodrug which is dephosphorylated to the active cytoprotective thiol metabolite. The elimination half-life of the... 

Clopidogrel is converted to an active thiol metabolite by several CYP isoforms, including 3A4 this then binds rapidly and irreversibly with platelet adenosine diphosphate receptors, thus inhibiting platelet aggregation, At present, inhibition of the antiplatelet effects of clopidogrel by atorvastatin represents a formulated but untested hypothesis, and these agents maybe administered concurrently. 

Figure 20.5 Metabolic activation of clopidogrel (12) in humans. A small part of a dose is activated by CYP3A to 2-oxo-clopidogrel (13), followed by hydrolytic ring opening to the active agent, a highly reactive thiol metabolite (14) that irreversibly antagonizes platelet ADP receptors via a covalent S-S bridge [31, 32].

Studies have recently addressed the cytotoxicity of uranyl acetate in primary rat cortical neuron cultures. Researchers found no evidence that uranyl acetate at concentrations less than 100 pM caused cytotoxicity (Jiang et al., 2007 Aschner and Jiang, 2009). Furthermore, there was no significant change in the levels of F2-isoprostanes, biomarkers of oxidative stress, as well as thiol metabolite levels on treatment with uranium. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium... 

British investigators (Haddow and Timmis 1951) synthesized and studied esters of the methanesulfonic acid. The most active derivative was the dimethylsulfonic ester of 1,4-butanedione, known as busulfan. Busulfan interacts with the thiol groups of proteins and amino acids some of its metabolites can alkylate the thiols of cysteine, peptides and proteins. Busulfan exerts selective cytotoxic activity in hematopoietic bone marrow cells and inhibits the formation of granulocytes and platelets. It slightly affects the lymphoid tissue. 

The degradation of tetrachloromethane by a strain of Pseudomonas sp. presents a number of exceptional features. Although was a major product from the metabolism of CCI4, a substantial part of the label was retained in nonvolatile water-soluble residues (Lewis and Crawford 1995). The nature of these was revealed by the isolation of adducts with cysteine and A,A -dimethylethylenediamine, when the intermediates that are formally equivalent to COClj and CSClj were trapped—presumably formed by reaction of the substrate with water and a thiol, respectively. Further examination of this strain classified as Pseudomonas stutzeri strain KC has illuminated novel details of the mechanism. The metabolite pyridine-2,6-dithiocarboxylic acid (Lee et al. 1999) plays a key role in the degradation. Its copper complex produces trichloromethyl and thiyl radicals, and thence the formation of CO2, CS2, and COS (Figure 7.64) (Lewis et al. 2001). 

In contrast to the lability of certain dN adducts formed by the BHT metabolite above, amino acid and protein adducts formed by this metabolite were relatively stable.28,29 The thiol of cysteine reacted most rapidly in accord with its nucleophilic strength and was followed in reactivity by the a-amine common to all amino acids. This type of amine even reacted preferentially over the e-amine of lysine.28 In proteins, however, the e-amine of lysine and thiol of cysteine dominate reaction since the vast majority of a-amino groups are involved in peptide bonds. Other nucleophilic side chains such as the carboxylate of aspartate and glutamate and the imidazole of histidine may react as well, but their adducts are likely to be too labile to detect as suggested by the relative stability of QMs and the leaving group ability of the carboxylate and imidazole groups (see Section 9.2.3). 

Mesna -thiol uroprotectant (binds and inactivates toxic metabolite acrolein) -nausea and vomiting -rash -headache -fatigue and lethargy ... 

Methods for determination of thiol drugs (i.e., captopril [21-25], penicillamine [26-28], hydrochlorothiazide [24, 25, 29, 30], and tiopronin [31, 32]) have been developed. These methods are based on CL from a cerium (IV) oxidation system sensitized by adequate fluorophores such as quinine and rhodamine B. By using HPLC-coupled CL-flow-injection analysis method, tiopronin and its metabolite 2-mercaptopropionic acid in human urine were sensitively determined with the detection limits of 0.8 and 1 pM, respectively [32],... 

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