Elimination kinetics of disulfiram in alcoholics after single and repeated doses.

Elimination kinetics of disulfiram were determined in 15 male alcoholics after 250 mg disulfiram taken by mouth as a single dose and again after 12 days of dosing. Apparent t 1/2s were calculated for disulfiram, diethyldithiocarbamate (DDTC), diethyldithiocarbamate-methyl ester (DDTC-Me), diethylamine (DEA), and carbon disulfide (CS2) and were found to be 7.3, 15.5, 22.1, 13.9, and 8.9 hr. Elimination t 1/2 for CS2 in breath was 13.3 hr. Average time to reach maximal plasma concentration after either single or repeated doses was 8 to 10 hr for disulfiram, DDTC, DDTC-Me, DEA, and CS2 in breath, while plasma CS2 concentration peaked 5 to 6 hr after disulfiram. In these studies, 22.4% and 31.3% of the disulfiram after single and repeated dosing was eliminated in the breath during one dosing interval. In urine, 1.7% and 8.3% of the disulfiram dose was eliminated as DDTC-glucuronide after single and repeated dosing, while DEA accounted for 1.6% and 5.7% of the dose. There was marked intersubject variability in plasma levels of disulfiram and its metabolites. This variability may be the result of the lipid solubility of disulfiram, differences in plasma protein binding, or the effect of enterohepatic cycling.

Elimination characteristics of disulfiram over time in five alcoholic volunteers: a preliminary study.

The authors studied the elimination of disulfiram and its metabolites for 24 hours after disulfiram administration in five healthy male alcoholic volunteers. Using high-performance liquid chromatography, they found that a single 500-mg dose resulted in a gradual increase in plasma disulfiram and its metabolites, with peak levels generally occurring 8 hours after dosing. There was considerable interpatient variability (e.g., in one volunteer no disulfiram was detected during the entire 24-hour sampling period). The authors also found that breath carbon disulfide was 9.1% of the dose of disulfiram administered, which is less than that expected theoretically.

Diethylthiocarbamic acid methyl ester. A potent inhibitor of aldehyde dehydrogenase found in rats treated with disulfiram or diethyldithiocarbamic acid methyl ester.

Rats were treated with disulfiram (Antabuse, DSF) or its metabolite diethyldithiocarbamic acid methyl ester (Me-DDC) and challenged with ethanol. The blood pressure response to ethanol was followed and blood was analyzed for DSF, Me-DDC and diethyldithiocarbamic acid (DDC). The rat liver aldehyde dehydrogenase (ALDH) isozyme activities were measured 2 hr after the ethanol challenge. Both treatments produced a significant fall in the blood pressure when challenged with ethanol, probably caused by a marked decrease in hepatocyte low Km and high Km activities. The mean plasma concentration ranges of Me-DDC and DDC were found to be 49-1241 nmol/l and 182-841 nmol/l, respectively, whereas DSF was undetectable. In addition, it was found that inactivation of hepatocyte low Km ALDH activity was dependent on preoxidation of Me-DDC by the microsomal cytochrome P-450 mixed function oxidases. Me-DDC was found to be oxidized under aerobic conditions in the presence of NADP to form diethylthiocarbamic acid methyl ester (Me-DTC). The structure was confirmed from its MS/EI fragmentation spectrum. Me-DTC was found to be a potent inhibitor of low Km ALDH when added to rat liver homogenate. The compound was also identified as a metabolite in rat blood collected from the DSF and Me-DDC treated rats, and in blood from human alcoholics on DSF treatment. Me-DTC appears to be more selective for the low Km isozymes whereas the opposite seems to be the case for the hydrolytic product, DTC.

High-dose cisplatin with diethyldithiocarbamate (DDTC) rescue therapy: preliminary pharmacologic observations.

Diethyldithiocarbamate (DDTC), a chelating agent that is a major metabolite of disulfuram, has been proposed as a potential rescue agent to reduce toxicity following high-dose cisplatin (HDCP) therapy. In the present study, we examined the pharmacologic interaction of HDCP and DDTC given as rescue therapy. Total plasma platinum and ultrafiltrate platinum pharmacokinetics and DDTC levels were determined in six patients with advanced malignancies who received a total of 11 cycles of HDCP with DDTC rescue. HDCP therapy (200 mg/m2 per cycle) consisted of 100 mg/m2 reconstituted in 250 cc 3% saline and infused over 3 h on days 1 and 8 of each 28-day cycle. DDTC rescue at a dose of 4 gm/m2 was given by an i.v. infusion (duration 1.5-3.5 h), beginning 45 min after the completion of cisplatin infusion. Peak total and ultrafiltrate levels and cisplatin pharmacokinetics in this study were indistinguishable from those of previous studies using the same HDCP regimen without DDTC rescue. Ultrafiltrate or unbound plasma platinum was less than 10% of total plasma platinum concentrations and demonstrated a biphasic pattern of elimination. Levels of DDTC predicted to be chemoprotective (greater than 400 microM) were achieved with the dose and schedule used in this study. These data demonstrate that DDTC can be targeted to protective plasma concentrations without significantly altering plasma cisplatin pharmacokinetics and support the potential usefulness of DDTC as a rescue agent following HDCP therapy.

Rapid degradation of disulfiram by serum albumin.

Interaction of disulfiram (DSF, tetraethylthiuram disulfide) with human plasma and albumin was studied by high performance liquid chromatography. Incubation of DSF with plasma resulted in a rapid reduction of the parent drug into diethyldithiocarbamate (DDC). At initial stages of incubation about one half of DDC in the reaction mixture was bound to protein. On further incubation, concentration of protein-bound DDC exceeded the concentration of free DDC. Similar results were obtained when DSF was incubated with bovine serum albumin (BSA) indicating that albumin is the major component of human plasma involved in the reduction of DSF. These data have implications both for the laboratory assay of DSF in human plasma and for the therapeutic use of the drug. When assaying the drug in plasma or serum, DSF standards prepared in protein solution for calibration should take into account the distribution of DSF into the parent drug and its derivatives in a time and protein concentration dependent manner. In a clinical setting, patients with a low serum albumin concentration might require small doses of DSF to achieve an optimal therapeutic effect.

Determination of disulfiram and its metabolites in human blood.

This work was initiated by the lack of a sensitive method for the determination of disulfiram and its metabolites in blood of patients treated with this drug. A method is described which allows the separate determination of carbon disulfide, free diethyldithiocarbamate and disulfides derived from disulfiram with adequate precision in 10 ml patient blood. It is based on a spectrophotometric determination of a yellow compound formed by trapping carbon disulfide produced from diethyldithiocarbamate and disulfiram in an ethanolic solution of diethylamine and copper(II)-acetate. Good quantitation of disulfiram and diethyldithiocarbamate in blood was achieved by trapping carbon disulfide produced when formic acid and cystein were added to the samples. During daily administration of 200 mg disulfiram to humans, concentrations of zero to 0.6 mug carbon disulfide and 0.2 to 1.0 mug diethyldithiocarbamate per ml blood were found using this method.

[Modifications of disulfiram and its metabolites in blood in alcoholic hepatopathy (author's transl)]. / Modifications des taux sanguins du disulfiram et de ses métabolites dans l'insuffisance hépato-cellularie d'origine alcoolique.

In cirrhotic, steatosic and healthy subjects, the authors studied the metabolism of disulfiram (TETD) administrated orally (500 mg) 3 consecutive days. Carbon disulfide (CS2) and the whole TETD, diethyl dithiocarbamate (DDC) disulfides, were determined by a gas chromatographic method. The evolution of metabolites is similar in steatosic and healthy subjects. In cirrhotics the CS2, DDC and disulfides level increase within the 3 days. This phenomenon may be related with hepatic toxicity of TETD and with the persistence of disulfiram-alcohol reaction. The authors suggest to use low doses of disulfiram in cirrhotic.

Quantitative analysis of disulfiram and its metabolites in human blood by gas-liquid chromatography.

A simple method is described that permits the direct quantitative determination of carbon disulphide, free diethyldithiocarbamate and disulphides derived from disulfiram in 1 ml of a patient's blood. It is based on a gas chromatographic determination of carbon disulphide produced from diethyldithiocarbamate and disulfiram using the head-space technique and a flame-photometric detector. The method is compared with a recently described spectrophotometric method.

The rapid reduction of disulfiram in blood and plasma.

A gas chromatographic assay procedure was developed to quantitate the reduction product of disulfiram, diethyldithiocarbamate (DDC), in blood and plasma. The procedure involved the in situ methylation of DDC prior to the extraction and chromatography of the methyl ester. The minimal sensitivity achieved was 0.2 microgram/ml from 1 ml of blood or plasma. The coefficient of variation about any concentration was 10.5%. Calibration curves having a reproducible nonlinear form were prepared up to 9 microgram/ml. The assay procedure was used to evaluate the stability of disulfiram and DDC in blood. Disulfiram was rapidly and quantitatively reduced to DDC within 4 minutes. The DDC thus formed decomposed in human and dog blood with half-lives of 70 and 100 minutes, respectively. The implications of these findings are discussed with respect to the chemical form of disulfiram responsible for the ethanol-sensitizing effect.

Rapid and sensitive on-line precolumn purification and high-performance liquid chromatographic assay for disulfiram and its metabolites.

The disulfiram (Antabus) metabolites diethyldithiocarbamate, diethyldithiocarbamate methyl ester, carbon disulphide and bis(diethyldithiocarbamato) copper complex were quantitatively analysed from directly injected heparin plasma by reversed-phase high-performance liquid chromatography. The highly volatile metabolite, carbon disulphide, was converted to the methyl ester of dimethyldithiocarbamate before chromatography. The analytical procedure is simple and does not require sample preparation or addition of an internal standard, and the compounds are eluted from the columns in 15 min. After automated on-line precolumn enrichment, the parent compound and biotransformation products could be back-flushed and chromatographed on an ordinary reversed-phase column. The influence of plasma protein binding on the constituents in the precolumn enrichment step was also investigated. Dissociation and partition of constituents from plasma proteins gave a complete retardation on the precolumn. The time courses of diethyldithiocarbamate and its methyl ester were followed in patients receiving therapeutic doses of disulfiram.

Determination of disulfiram and metabolites from biological fluids by high-performance liquid chromatography.

A high-performance liquid chromatographic method is described for the determination of disulfiram, diethyldithiocarbamate, diethyldithiocarbamate methyl ester, carbon disulfide, and diethylamine from a single sample of plasma or urine. The analytical procedure is based on a quantitative stepwise extraction of disulfiram and diethyldithiocarbamate methyl ester, or the conversion of diethyldithiocarbamic acid, carbon disulfide and diethylamine to diethyldithiocarbamate methyl ester for chromatographical determination. The procedure is specific, precise and simple. The application of the analytical methods developed for the determination of disulfiram and the various metabolites in plasma from mice given disulfiram intraperitoneally or humans given Antabuse orally is illustrated.

A rapid and simple radioactive method for the determination of disulfiram and its metabolites from a single sample of biological fluid or tissue.

An analytical method is described for the determination of radioactive disulfiram, diethyldithiocarbamate, diethyldithiocarbamate-methyl ester, diethyldithiocarbamate-glucuronide, inorganic sulfate, and a protein bound S35 fraction from a single sample of either plasma, urine or tissue. The procedure is based upon quantitative stepwise extraction or precipitation of the individual compounds, and is both specific and precise. The applicability of the methods developed for the determination of S35 disulfiram and its S35 metabolites in plasma and urine from a dog given S35 disulfiram i.v., and in mouse brain from mice given S35 disulfiram i.p. are illustrated.

Methods for detecting disulfiram in biologic fluids: application in studies of compliance and effect of divalent cations on bioavailability.

Studies regarding the efficacy of disulfiram in the treatment of alcoholism have not included a method of evaluating compliance to the prescribed regimen. This article outlines current methods used to detect disulfiram in blood, breath, and urine.

Radioactive and nonradioactive methods for the in vivo determination of disulfiram, diethyldithiocarbamate, and diethyldithiocarbamate-methyl ester.

Although disulfiram (tetraethylthiuram disulfide; DSF) has been used in the treatment of alcoholism for almost a quarter of a century, little is known about its in vivo metabolism. One reason for this is that few analytical methods are available that can determine DSF and its various metabolites in biologic fluids and tissues. This article describes two simple procedures for the determination of these substances.