Oral Administration Of Trimethadione Research Articles

Trimethadione as a probe drug to estimate hepatic oxidizing capacity in humans

Trimethadione (TMO) has the properties required of probe drugs for the evaluation of hepatic drug-oxidizing capacity in humans in vivo. TMO is demethylated to dimethadione (DMO), its only metabolite, in the liver after oral administration. Involvement of two cytochrome P450's—CYP2C9 and 3A4—in TMO metabolism has been seen in humans, but involvement of 1A2 is not clearly established. In humans with various types of liver disease and hepatectomy, the serum DMO TMO ratios, which were measured on blood samples obtained by a single collection 4 hr after oral administration of TMO, correlated well with the degree of hepatic damage. This finding suggests that TMO may be used as a probe drug in the rapid determination of the functional reserve mass of the liver as well as hepatic drug-oxidizing capacity in humans in vivo.

Trimethadione metabolism as a probe drug to estimate hepatic oxidizing capacity in rats

1. Trimethadione (TMO) has the properties required of probe drugs for the evaluation of hepatic oxidizing capacity in vivo. 2. TMO is demethylated to dimethadione (DMO), its only metabolite, in the liver after oral administration. 3. In rats with various types of hepatic intoxicated-, induced- and partially hepatectomized-rats, the serum DMO/TMO ratios, which were measured on blood samples obtained by a single collection 2 hr after oral administration of TMO, correlated well with the degree of hepatic damage or induction. 4. This finding suggests that TMO may be used as a probe drug in the rapid determination of the functional reserve mass of the liver as well as the hepatic oxidizing capacity.

Trimethadione tolerance test for the quantitative assessment of liver function in rats

The quantitative estimation of the hepatic functional volume in rats was attempted using the serum dimethadione (DMO)/trimethadione (TMO) ratio in a single blood sampling after oral administration of TMO, which we call the TMO tolerance test, in order to develop a means of pre-operatively assessing hepatic resectability. Serum DMO/TMO ratios correlated well with the total amount of the hepatic microsomal TMO-N-demethylase activity (enzyme activity) and with the remnant liver weight after 37% and 68% partial hepatectomy. These ratios increased after partial hepatectomy in parallel with the changes in the enzyme activity and the remnant liver weight. The results suggest that the quantitative functional changes of the remnant liver after hepatectomy in both CCl4-treated and untreated rats can be estimated pre-operatively by the TMO tolerance test.

The Impact of Liver Cirrhosis and Cholelithiasis on Phase I and II Reactions Using Antipyrine and Trimethadione as a Model Substrate.

Five male patients with extrahepatic cholelithasis and ten male patients with liver cirrhosis were administered simultaneously 4mg/kg trimethadione (TMO) and 500mg/man antipyrine (AP). Changes in phase I (AP and TMO) and phase II (AP) reactions of the model substrates in liver disease were examined. The patients with liver cirrhosis exhibited prolonged half-life (t1/2) and decreased metabolic clearance (CL) of AP when compared with cholelithasis patients, while no change was found in the apparent volume of distribution (Vd). The serum dimethadione (DMO)/TMO ratio at 4hr after oral administration of TMO was apparently decreased in the cirrhotic patients. The cirrhotic patients also exhibited significant decreases in urinary excretion and clearance for production of three major AP metabolites (4-hydroxyantipyrine, 3-hydroxymethyl-3-norantipyrine, and 3-hydroxymethylantipyrine), while no significant differences between the cirrhotic patients and cholelithasis patients were noted in percentages of either total or individual glucuronidation of these metabolites. These findings suggest that AP and TMO metabolisms (phase I) are severely impaired in cirrhotic patients, whereas glucuronidation of AP is unaffected (phase II).

Effect of dimethadione derived from repeated oral administration of trimethadione on pancreatic secretion in dogs

The effect of the weak organic acid of dimethadione (DMO) on secretin-stimulated pancreatic secretion was studied with repeated oral administration of trimethadione (TMO), the precursor of DMO, to dogs at a dose of 10 to 160mg/kg/day for a period of 14 days. The bicarbonate concentration in pancreatic juice at a steady state decreased significantly, reflecting a close correlation with the dose of TMO and DMO concentrations in plasma and pancreatic juice. The maximal decrement from the control of cases of no TMO administration was 18.8 mEq/l (12.1% of the control level). The chloride concentration in pancreatic juice showed a reciprocal relation to the bicarbonate concentration. The sum of both anion concentration was constant, irrespective of the dose of TMO. The average carbon dioxide tension of pancreatic juice in all doses of TMO was lower than that of the control, but differences were not statistically significant. The pH, flow rate, sodium and potassium concentrations in pancreatic juice at a steady state did not differ significantly in relation to the dose of TMO. These findings suggest that repeated oral administration of TMO cause a significant decrease in bicarbonate concentration in pancreatic juice, resulting probably from the buffer action of bicarbonate on protons provided from the undissociated form of DMO.

Pancreatic Excretion of Dimethadione and Trimethadione by Repeated Oral Administration of Trimethadione in Dogs

To examine pancreatic excretion of dimethadione (DMO), a weak organic acid, as well as of its precursor trimethadione (TMO), TMO was given orally to dogs with pancreatic fistulae at a dose of 10-160 mg/kg/day over a period of 14 days. Blood samples were taken once a day during the administration of TMO and for 7 days after discontinuation of the drug. On the 15th day, pancreatic juice was collected under stimulation by secretin (2 Crick-Haper-Raper units/kg/h). DMO concentration in plasma reached a maximal plateau around the 10th day after starting TMO administration, and depended directly on the dose of TMO. Pancreatic excretion of DMO at a steady state closely depended on both the dose of TMO and the DMO concentration in plasma. The pancreatic juice/plasma concentration ratio for DMO exceeded 1.0 at a steady rate and decreased with the increased flow rate. Pancreatic DMO clearance (DMO output/DMO concentration in plasma) increased, depending on the flow rate, the bicarbonate concentration, and pH of pancreatic juice. Pancreatic excretion of TMO was zero or extremely low.

Induction of cytochrome p-450 and related drug-oxidizing activities in muscone (3-methylcyclopentadecanone)-treated rats

In the present study, we investigated the effects of muscone on both in vitro and in vivo parameters of the hepatic microsomal drug-metabolizing enzyme system and other enzyme activities in rats. In the in vivo study, the serum dimethadione (DMO)/trimethadione (TMO) ratios at 2 hr after oral administration of TMO (100 mg/kg) were significantly increased in both male and female rats treated with 75 and 150 but not 40 mg muscone/kg. Antipyrine metabolite profile in 24 hr urine of rats pretreated with muscone (150 mg/kg) was examined. The results showed that the excretion of norantipyrine was significantly increased as compared to the control group. In the in vitro study, we found that the content of cytochrome P-450, and activities of aminopyrine N-demethylase, aniline hydroxylase and δ-aminolevulinic acid (ALA) synthetase were significantly increased as compared to the controls in both male and female rats treated with muscone (75 and 150 mg/kg). This type of induction of the hepatic metabolizing enzymes was similar to that seen after treatment with a prototype drug, phenobarbital.

Trimethadione metabolism in patients with normal liver and in patients with chronic liver disease.

Serum dimethadione (DMO)/trimethadione (TMO) ratios after oral administration of TMO have been investigated in 10 patients with normal livers, 8 patients with hepatoma and 8 patients with hepatoma and cirrhosis. Serum concentration ratios of DMO to TMO at 4 h after oral administration of TMO in patients with chronic liver disease were significantly decreased by 27% for those with hepatoma and 52% for those with hepatoma and cirrhosis. Serum DMO/TMO ratios at 4 h correlated well with liver function characteristics (total protein r = 0.741, plasma albumin r = 0.826, total bilirubin r = -0.725, cholinesterase r = 0.853) as well as with pharmacokinetic parameters (total body clearance r = 0.852, half-life r = -0.636) in both patients with normal livers and patients with chronic liver disease. This study suggests that serum DMO/TMO ratios in a blood sample obtained by a single collection after an oral administration of TMO might provide a clinically useful index of the hepatic drug-oxidizing capacity in an individual patient with chronic liver disease without determining the liver function characteristics or the pharmacokinetic parameters.

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抗てんかん薬Ｔｒｉｍｅｔｈａｄｉｏｎｅ（ＴＭＯ）による経口すい石溶解療法

Trimethadione tolerance test for evaluation of functional reserve of the liver in patients with liver cirrhosis and esophageal varices.

Dimethadione (DMO)/trimethadione (TMO) ratios in serum after oral administration of TMO were investigated in 15 normal subjects and in 20 patients with cirrhosis and esophageal varices. Severe impairment of liver function was associated with a decrease in total cholesterol, total protein and plasma albumin, or an increase in total bilirubin, serum glutamic oxaloacetic transaminase, serum glutamic pyruvic transaminase, serum gamma-glutamyl transpeptidase and indocyanine green retention rate (ICG R15). Serum concentration ratios of DMO to TMO at 2 or 4 h after oral administration of TMO in patients were significantly decreased by 67 or 66%, respectively, compared to normal subjects. DMO/TMO ratios at 2 or 4 h following oral administration of TMO were well correlated with the liver function parameters (plasma albumin r = 0.758 at 2 h, r = 0.776 at 4 h; total protein r = 0.613 at 2 h, r = 0.619 at 4 h; ICG R15 r = -0.683 at 2 h, r = -0.746 at 4 h, in patients only; cholinesterase r = 0.873 at 2 h, r = 0.908 at 4 h) as well as with pharmacokinetic parameters (total body clearance r = 0.794 at 2 h, r = 0.786 at 4 h) in both the normal subjects and the patients. It suggests that the DMO/TMO ratio obtained in a single blood sample collected after oral administration of TMO might provide a useful measure for function hepatic reserve.

Saliva levels of trimethadione and its metabolite as an index of drug metabolizing activity in rats.

1. It was investigated in normal and liver-injured rats administered with trimethadione (TMO) as to whether concentrations of TMO in plasma are able to be predicted from the corresponding saliva levels. 2. The saliva/plasma (S/P)ratio of TMO was about 1, while its metabolite 5,5-dimethyl-2,4-oxazolidinedione (DMO) showed a S/P ratio of 0.65. 3. In normal rats, there was a high correlation between saliva and plasma concentration of TMO and DMO. (TMO: r=0.966, DMO: r=0.950). 4. In liver-injured pretreated rats with carbon tetrachloride, alpha-naphthyl isothiocyanate or D-galactosamine, there was a high correlation between the saliva DMO/TMO ratio and the plasma DMO/TMO ratio after oral administration of TMO (r=0.983 at 1 h, r=0.952 at 2 h). 5. The saliva DMO/TMO ratio, as well as the plasma DMO/TMO ratio, may be utilized as an index of drug-metabolizing activity of the liver.

Pharmacokinetic studies of trimethadione and its metabolite in rats with chemical-induced liver injury.

A rapid and sensitive gas-liquid chromatographic procedure was developed for the measurements of trimethadione (TMO) and its metabolite, 5, 5-dimethyl-2, 4-oxazolidine-dione (DMO) in plasma. TMO and DMO were extracted from plasma by a micro-extraction method and chromatographed on a 10% Carbowax 6000 column using paramethadione as an internal standard. Recoveries of TMO and DMO ranged from 96 to 104% using a 0.1 ml of plasma. The method is capable of measuring at least 5 microgram of TMO and DMO per milliliter. After an oral administration of TMO at a dose of 100 mg/kg, mean plasma levels of TMO and DMO in 6 rats reached a peak of 98 microgram/ml at 0.6 h and 163 microgram/ml at 8 h and declined with a half-life of 2.2 h and 39.4 h, respectively. After the intravenous administration of TMO at a dose of 100 microgram/kg, half-lives of TMO and DMO were 2.5 h and 39.1 h, respectively. Pretreatment of rats with carbon tetrachloride, d-galactosamine amd alpha-naphthyl isothiocyanate, prolonged T 1/2 and Tmax of TMO, reduced the Km value and increased the AUC. These results suggest that plasma levels of TMO and DMO might be useful as an index of drug metabolizing capacity in animal and man.

Pancreatic excretion of 5, 5-dimethyl-2, 4-oxazolidinedione in normal subjects.

Pancreatic excretion of 5,5-dimethyl-2,4-oxazolidinedione (DMO) was studied in 25 normal subjects using the technique of the traditional pancreatic secretory test. The pancreozymin-secretin test was performed 4 days after the oral administration of trimethadione (3,5,5-trimethyl-2,4-oxazolidinedione, the precursor of DMO) for 3 consecutive days. When a dose of 1 unit/kg of pancreozymin was administered intravenously, both DMO concentration and output of a 10-min fractional specimen were rapidly increased and then decreased gradually. When a dose of 1 unit/kg of secretin was injected 30 min after pancreozymin, DMO concentration in duodenal aspirate showed no significant alteration, while DMO output of the aspirate was remarkably increased and then diminished in parallel to flow rate. DMO concentration in plasma varied widely from subject to subject, but was fairly constant during the course of the test in the same subject. Total DMO output in the postpancreozymin 30-min and postsecretin 60-min periods was linearly related to plasma DMO concentration. The output of DMO, when expressed as the output at a level of 10 mg/100 ml of plasma DMO, was linearly related to secretory volume and bicarbonate and amylase outputs in the postsecretin period. These results led to the conclusion that the human pancreas was capable of excreting a week organic acid of DMO with a molecular weight of 129.1 and that the excretion of DMO in normal subjects was a funciton of two factors: plasma DMO concentration and pancreatic secretory volume.