Journal ArticleDOI
A review of the pharmacokinetics and pharmacodynamics of disulfiram and its metabolites.
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In patients with alcohol‐related severe hepatocellular damage, the oxidative P 450 catalyzed formation of the Me‐DTC and probably also of its sulfoxide and sulphone metabolites is impaired, and thus inactivation of ALDH activity in the liver appears to be delayed or even completely absent.Abstract:
After ingestion, disulfiram (DSF) is rapidly converted, probably in the stomach, to its bis (diethyldithiocarbamato) copper complex. Consequently, absorption and distribution via the gastrointestinal mucosa into the blood might involve both the parent drug and its copper complex. In the blood, both compounds are rapidly degraded to form diethyldithiocarbamic acid (DDC), which is unstable and is further degraded to form diethylamine and carbon disulphide. DDC is also a substrate of phase II metabolism, which involves formation of diethyldithiomethylcarbamate (Me-DDC) and the glucuronic acid of DDC. Me-DDC also undergoes oxidative biotransformation to diethylthiomethylcarbamate (Me-DTC), which is further oxidized to its corresponding sulphoxide and sulphone metabolites. Me-DTC may to act as a suicide inhibitor with a preference for the mitochondrial low Km isozyme of aldehyde dehydrogenases (ALDH 1), whereas the two S-oxidized metabolites, especially the sulfone metabolite, are more potent inhibitors not only of ALDH 1, but also of the cytosolic high Km isozyme of ALDH (ALDH 2). The inhibitory reaction between the enzyme and each of the three metabolites is characterized by a covalent adduct formation, probably with the cysteine residue at the active site of the enzymes. The adduct formed is nonreducible at a physiological concentration of glutathione, and inactivation in the presence of this endogenous tripeptide was increased by action in vitro of the sulphoxide and sulphone metabolites. Those findings are all in concordance with the in vivo observations made on DSF. In human volunteers treated with increasing doses of DSF and challenged with ethanol between each of the dosage periods, the mean plasma concentrations of Me-DTC at steady state were proportional to the DSF doses given. There was also a close relationship between increased oxidative metabolic formation of Me-DTC, high oxidative formation of acetaldehyde, and the full complements of a valid disulfiram ethanol reaction (DER). Consequently, Me-DTC in plasma may not only serve as a marker of the oxidative metabolic function of the liver, but also of the therapeutic effectiveness of the treatment in subjects at steady state. Obviously, there is a need for individual dose-titration regimens. In patients with alcohol-related severe hepatocellular damage, the oxidative P 450 catalyzed formation of the Me-DTC and probably also of its sulfoxide and sulphone metabolites is impaired, and thus inactivation of ALDH activity in the liver appears to be delayed or even completely absent. The consequence for the patient may be an insufficient DER.(ABSTRACT TRUNCATED AT 400 WORDS)read more
Citations
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Journal ArticleDOI
Consensus Guidelines for Therapeutic Drug Monitoring in Neuropsychopharmacology: Update 2017.
Christoph Hiemke,Niels Bergemann,Hans-Willi Clement,Andreas Conca,Jürgen Deckert,Katharina Domschke,Gabriel Eckermann,Karin Egberts,Manfred Gerlach,Christine Greiner,Gerhard Gründer,E Haen,Ursula Havemann-Reinecke,Gudrun Hefner,Renate Helmer,Ger Janssen,Eveline Jaquenoud,Gerd Laux,Thomas Messer,Rainald Mössner,Matthias J. Müller,Michael Paulzen,Bruno Pfuhlmann,P. Riederer,Alois Saria,Bernd Schoppek,Georgios Schoretsanitis,Markus J. Schwarz,M. Silva Gracia,Benedikt Stegmann,Werner Steimer,Julia C. Stingl,Manfred Uhr,S. Ulrich,Stefan Unterecker,R. Waschgler,Gerald Zernig,Gabriele Zurek,Pierre Baumann +38 more
TL;DR: Following the new guidelines for therapeutic drug monitoring in psychiatry holds the potential to improve neuropsychopharmacotherapy, accelerate the recovery of many patients, and reduce health care costs.
Journal ArticleDOI
AGNP Consensus Guidelines for Therapeutic Drug Monitoring in Psychiatry: Update 2011
Christoph Hiemke,Pierre Baumann,Niels Bergemann,Andreas Conca,Otto Dietmaier,Karin Egberts,Miriam Fric,Manfred Gerlach,Christine Greiner,Gerhard Gründer,E Haen,Ursula Havemann-Reinecke,E. Jaquenoud Sirot,H. Kirchherr,Gerd Laux,U. C. Lutz,Thomas Messer,Matthias J. Müller,Bruno Pfuhlmann,Bernhard Rambeck,P. Riederer,Bernd Schoppek,Julia C. Stingl,Manfred Uhr,S. Ulrich,R. Waschgler,Gerald Zernig +26 more
TL;DR: Following guidelines for TDM in psychiatry will help to improve the outcomes of psychopharmacotherapy of many patients especially in case of pharmacokinetic problems, and one should never forget that TDM is an interdisciplinary task that sometimes requires the respectful discussion of apparently discrepant data.
Journal ArticleDOI
Targeting copper in cancer therapy: ‘Copper That Cancer’
Delphine Denoyer,Shashank Masaldan,Sharon La Fontaine,Sharon La Fontaine,Michael A. Cater,Michael A. Cater +5 more
TL;DR: The biological importance of copper and copper homeostasis in mammalian cells is outlined, followed by a discussion of the current understanding of copper dysregulation in cancer, and the recent therapeutic advances using copper coordination complexes as anticancer agents.
Journal Article
AGNP consensus guidelines for therapeutic drug monitoring in psychiatry: update 2011
Christoph Hiemke,Pierre Baumann,Niels Bergemann,Otto Dietmaier,Karin Egberts,Miriam Fric,Manfred Gerlach,C Greiner,Gerhard Gründer,E Haen,Ursula Havemann-Reinecke,E. Jaquenoud Sirot,H. Kirchherr,Gerd Laux,U. C. Lutz,Thomas Messer,Matthias J. Müller,Bruno Pfuhlmann,Bernhard Rambeck,P. Riederer,Bernd Schoppek,Julia C. Stingl,Manfred Uhr,S. Ulrich,R. Waschgler,Gerald Zernig,Andreas Conca +26 more
TL;DR: Following guidelines for TDM in psychiatry will help to improve the outcomes of psychopharmacotherapy of many patients especially in case of pharmacokinetic problems, and one should never forget that TDM is an interdisciplinary task that sometimes requires the respectful discussion of apparently discrepant data.
Journal Article
Disulfiram, a clinically used anti-alcoholism drug and copper-binding agent, induces apoptotic cell death in breast cancer cultures and xenografts via inhibition of the proteasome activity.
TL;DR: This study shows that inhibition of the proteasomal activity can be achieved by targeting tumor cellular copper with the nontoxic compound DSF, resulting in selective apoptosis induction within tumor cells.
References
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Journal Article
Liver alcohol dehydrogenase and aldehyde dehydrogenase in the Japanese: isozyme variation and its possible role in alcohol intoxication.
TL;DR: A high incidence in the Japanese of the unusual phenotype of ALDH, which lacks in the low Km isozyme, suggests that the initial intoxicating symptoms after alcohol drinking in these subjects might be due to delayed oxidation of acetaldehyde rather than its higher-than-normal production by typical or atypical ADH.
Journal ArticleDOI
Human aldehyde dehydrogenase: mechanism of inhibition of disulfiram
TL;DR: Disulfiram labeled with carbon-14 reacts specifically with human liver aldehyde dehydrogenase E1 with loss of catalytic activity and no incorporation of label, and diethyldithiocarbamate is formed.
Book ChapterDOI
The Role of Acetaldehyde in the Actions of Ethanol
TL;DR: Criteria is examined critically and some of the recent evidence which supports a possible role of this metabolite in the actions of ethanol is reviewed.