Trimethadione Research Articles

Effects of cimetidine and diethylaminoethyl 2,2-diphenylvalerate HCL (SKF 525-A) on trimethadione metabolism in the rat.

The effects of cimetidine and diethylaminoethyl 2,2-diphenylvalerate (SKF 525-A) on trimethadione (TMO) metabolism were examined in the rat. The pretreatment of rats with cimetidine (100 mg/kg, i.p.) or SKF 525-A (40 mg/kg, i.p.) resulted in a prolongation of half-life (T1/2), an increase in the area under the curve (AUC) and a decrease in the total body clearance (CL) of TMO. However, the apparent volume of distribution (Vd) of TMO was not changed. The activities of hepatic cytochrome P-450-dependent drug-oxidizing enzymes such as aminopyrine and TMO N-demethylase, and aniline hydroxylase activities were decreased by pretreatment of rats with cimetidine or SKF 525-A. Cytochrome P-450 contents were not changed. The inhibition of aminopyrine and TMO N-demethylase activities in the rat pretreated with cimetidine or SKF 525-A was noncompetitive. These results suggest that cimetidine and SKF 525-A inhibited TMO metabolism in a similar manner to the rat pretreated with their doses.

The effect of indomethacin on hepatic drug-oxidizing capacity in the rat: trimethadione and antipyrine metabolism as an indicator.

In this study, trimethadione (TMO) and antipyrine were chosen as model drugs to investigate the extent of hepatic drug-oxidizing capacity. It was also studied whether pretreatment of rats with indomethacin affected the formation of antipyrine metabolite. Pretreatment with indomethacin in a dose of 5 mg/kg/d for 3 d did not change the serum half-life (T1/2), the total body clearance (CL), and the apparent volume of distribution (Vd) of TMO and antipyrine. However, in the rat treated with 8.5 mg/kg/d for 3 d of indomethacin, these parameters were significantly decreased as compared to controls except to Vd values in antipyrine kinetics in vivo. The contents of cytochrome P-450, and the activities of aminopyrine N-demethylase and aniline hydroxylase were not changed by 5 mg/kg/d for 3 d of indomethacin. However, in the rat treated with 8.5 mg/kg/d for 3 d of indomethacin, these enzyme activities were significantly decreased as compared to controls. The activities of heme oxygenase were significantly increased as compared to controls in the rat treated with 5 and 8.5 mg/kg/d for 3 d of indomethacin, in vitro. The excretions of 4-hydroxyantipyrine and 3-hydroxymethyl antipyrine were not changed in the rat treated with 8.5 mg/kg for 3 d of indomethacin as compared to controls, whereas the excretion of norantipyrine was significantly decreased. These results, together with the previous findings, indicate that indomethacin treatment inhibited N-demethylation pathway of TMO and antipyrine metabolism.

Simultaneous determination of trimethadione and its metabolite in rat and human serum by high-performance liquid chromatography

Recently we reported a sensitive method for the determination of low concentrations of trimethadione (TMO) and its metabolite, 5,5-dimethyl-2,4-oxazolidinedione (DMO), by using gas chromatography (GC) with flame-therm-ionic detection (FTD) [1]. In addition, a pharmacokinetic study using this sensitive method was carried out in carbon tetrachloride-treated rats [1]. However, GC methods for the determination of TMO and DMO in rat plasma normally are time-consuming. In this present study, we report the development of a rapid and selective high-performance liquid chromatographic (HPLC) method for the simultaneous analysis of TMO and DMO in rat and human serum.

A method for estimation of hepatic drug-metabolizing capacity: determination of concentration of trimethadione and its metabolite in human serum.

There have been significant correlations between serum concentration ratios of 5,5-dimethyl-2,4-oxazolidinedione (Dimethadione, DMO)/trimethadione (TMO) after administration of TMO and hepatic microsomal cytochrome P-450 contents in rats with various treatments (CCl4 or phenobarbital). The pharmacokinetics of TMO and DMO, and the serum concentration ratio of DMO/TMO have been investigated in healthy volunteers after oral administration of 1 mg/kg (N = 4), 2 mg/kg (N = 6) and 4 mg/kg (N = 6) TMO, respectively. TMO and DMO concentrations in serum were determined by a gas-liquid chromatographic method. Serum disappearance of TMO was described by one compartment model. The T1/2, Kel, Vd and C1 of TMO and of DMO were shown to have almost the same values in 2 mg/kg or 4 mg/kg TMO administration. Correlation coefficient between DMO/TMO ratio in serum and time course after 1 mg/kg, 2 mg/kg and 4 mg/kg TMO administration was found to be r = 0.958, r = 0.924 and r = 0.938, respectively. These results indicate that the serum concentration ratio of DMO/TMO, especially at 2 or 4 h after 4 mg/kg TMO administration orally, may be an index of hepatic drug-metabolizing capacity in human serum as well as in rats.

P-389) - The effect of phenobarbital on trimethadione metabolizing enzyme in human

P-389) - The effect of phenobarbital on trimethadione metabolizing enzyme in human

Relationship between trimethadione metabolism and hepatic drug-oxidizing enzyme activities in different animal species.

The purpose of this investigation is to correlate between trimethadione (TMO) metabolism and hepatic microsomal drug-oxidizing activities in different animal species (mouse, hamster, rat and rabbit). A good correlation was obtained between the plasma concentration ratio of 5,5-dimethyl-2,4-oxazolidinedione (DMO) to TMO and relative activities of aminopyrine (r = 0.999 at 1 h, p less than 0.01; r = 0.994 at 2 h, p less then 0.01) and TMO (r = 0.988 at 1 h, p less than 0.02; r = 0.975 at 2 h, p less than 0.05) N-demethylase, and aniline (r = 0.993 at 1 h, p less than 0.01; r = 0.979 at 2 h, p less than 0.01) hydroxylase. These results indicate that the values of plasma DMO/TMO ratio determined at an appropriate time period following its administration would be reflecting the degree of hepatic drug-oxidizing capacity in various experimental animal species. These findings thus suggest that in vivo TMO metabolism would be a useful drug for predicting hepatic drug-oxidizing capacity in humans.

Relationship between trimethadione metabolism and hepatic drug-metabolizing enzyme activities in different animal species.

The purpose of this investigation is to determine the correlations between trimethadione (TMO) metabolism and hepatic microsomal drug-oxidizing activities in different animal species (mouse, hamster, rat and rabbit). A good correlation was obtained between the plasma concentration ratio of 5,5-dimethyl-2,4-oxazolidinedione (DMO) to TMO and relative activities of aminopyrine N-demethylase (r=0.999 at 1 h, p<0.01; r=0.994 at 2 h, p<0.01) and TMO N-demethylase (r=0.988 at 1 h, p<Tj.02; r=0.975 at 2 h, p<0.05), and aniline hydroxylase (r=0.993 at 1 h, p<0.01; r=0.979 at 2 h, p<0.01). These results indicate that the values of plasma DMO/TMO ratio determined at an appropriate time period following its administration would reflect the degree of hepatic drug-oxidizing capacity in various experimental animal species. These findings thus suggest that in vivo TMO metabolism would be a useful method for predicting hepatic drug-oxidizing capacity in humans.

Effect of acetazolamide on the anticonvulsant potency of several antiepileptic drugs in mice.

Effect of acetazolamide (AZA) on the anticonvulsant potency of several antiepileptics was investigated in mice by maximal electroshock seizure test. By the coadministration of AZA, a remarkable increase in the anticonvulsant activity was brought about not only for the barbiturates including barbital (BA), mephobarbital (MB) and metharbital (MET), but also for the other antiepileptics such as phenytoin (PHT), valproic acid (VPA) and trimethadione (TMO). This potentiating effect of AZA, however, was relatively weak for PHT, MET and TMO (about 2.5 fold) in contrast to those for phenobarbital (PHB), BA, MB and VPA (4-5 fold). The brain-serum concentration ratio (B/S) of PHB was elevated by the coadministration of AZA, while the B/S of PHT was not changed. Thus it was inferred that the difference in the potentiating effect of AZA on the activity of the antiepileptics was due to the difference in its effect on the brain levels of the antiepileptic drugs. However, the potentiating effect of AZA was still observed for PHT, VPA and MET, as well as PHB, in reserpinized mice. Therefore, some pharmacodynamic effect of AZA other than its increasing effect on the brain levels of the antiepileptic drugs may partly contribute to the potentiation of the activity of the antiepileptic drugs.

Studies on the trimethadione metabolism as a tool for the assessment of drug-metabolizing capacity using plasma and urine of rats pretreated with phenobarbital and 3-methylcholanthrene.

To determine whether concentrations of trimethadione (TMO) and its metabolite 5,5-dimethyl-2,4-oxazolidinedione (DMO) in plasma as well as in urine of rats are useful indicator of drug-metabolizing capacity or not, the following experiments were carried out. Plasma TMO and DMO concentrations were measured in phenobarbital (PB) or 3-methylcholanthrene (3-MC)-pretreated rats following the administration of TMO. In PB-pretreated rats, there was a good correlation between elimination rate constant (Kel and plasma DMO/TMO ratio; r = 0.991 at 1 h, r = 0.967 at 2 h). However, there was no good correlation in 3-MC-pretreated rats (r = 0.780 at 1 h, r = 0.720 at 2 h). TMO and DMO excretion in PB and 3-MC pretreated rats following the administration of TMO were not significantly different in 24-h urine. These experiments, together with the previous findings, indicate that concentrations of TMO and DMO in plasma, but not in urine, in PB-pretreated rats may be a useful indicator of drug-metabolizing capacity.

Trimethadione effects on cholinergic responses in Aplysia neurons

The anticonvulsant, trimethadione (TMO), was tested for effects on cholinergic responses to iontophoretic application of ACh on identified neurons in Aplysia. TMO (1–10 mM) depressed the amplitudes of depolarizing responses mediated by Na + and hyperpolarizing responses mediated by Cl − but did not affect hyperpolarizing responses mediated by K +. Such a combination of effects on cholinergic responses distinguishes the action of this anti-absence drug from agents effective against tonic-clonic seizures and from convulsant drugs.

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.

Metabolism and Disposition of Trimethadione in Pregnant Rats

The metabolism and disposition of a suspected human teratogen, trimethadione (TMO), was studied in pregnant rats following administration of the drug at doses of 60 and 240 mg/kg/day during 6 to 15 days of gestion, with a view to understanding the fetotoxicity of the drug. Following the last dose, animals were sacrificed at 6, 12, and 24 hr, and the fetuses were removed by caesarean section. The concentrations of TMO and its N-demethylated metabolite, dimethadione (DMO), were determined by a specific GLC procedure in maternal plasma, urine, brain, and liver, as well as in placenta and whole fetus. The plasma and liver concentrations of TMO and DMO suggested that the parent drug is rapidly converted to DMO. Total 24 hr urinary recoveries of the unchanged drug and the metabolite were 61 and 82% following 240 and 60 mg/kg/day doses of TMO, respectively. The DMO concentrations in brain and all other tissues analyzed were far greater than those of TMO. The fetus to maternal plasma concentration ratios of TMO suggested that the placental transfer of the drug was greater than the clearance from the fetus over the periods examined, whereas the transfer of the metablite seemed to be independent of dose. Furthermore, the rate of decline of DMO in fetus was far slower than that of the placenta and maternal plasma, causing accumulation of DMO in the fetus. The results suggest that the fetotoxic effects produced by TMO when given to pregnant rats could be due to accumulation of DMO in fetus.

The effect of trimethadione on brain energy metabolism and EEG activity of the conscious rat exposed to HPO

The use of trimethadione (TMO) as a protector in hyperbaric oxygen toxicity in the conscious rat has been examined in detail. The oxidation-reduction state of pyridine nucleotides was measured simultaneously with the EEG activity from the surface of the brain cortex. From the data obtained, a few parameters were calculated. The results show that in TMO-treated animals the time to the onset of convulsions, the time to the onset of NADH oxidation-reduction cycles, and the survival time were significantly longer than in the control group. The effect of TMO on the EEG shows that the tonic phase of the convulsive activity was almost completely abolished.

Quantitative evaluation of the pentylenetetrazol—Anticonvulsant interaction on the egg of the cat

The interaction of pentylenetetrazol (PTZ) with the anticonvulsants phenobarbital (PB), trimethadione (TD) and diphenylhydantoin (DPH) or saline on the EEG of the cat was examined with the aid of power spectral density analysis. Pretreatment with PB or TD effectively increased the dose of PTZ required for induction of paroxysmal activity, while some decrease in PTZ dose was seen with DPH pretreatment. A direct correlation was seen between the amplitude (normalized total power) increases and the amount of PTZ required to induce paroxysm with each pretreatment. Dominant hippocampal theta (4.0–4.5 Hz) which was induced by PTZ following saline or DPH pretreatment was reduced or eliminated following TD and PB pretreatments. The triggering of generalized and sustained bilateral seizural activity was suggested to occur because activity in multiple intermittent foci throughout the brain gradually build up to a necessary critical mass. PB and TD were suggested to act by increasing the critical mass required for triggering the paroxysm, while DPH was suggested to act by lowering the critical mass resuling in less severe ictal activity.

Trimethadione and Nephrosis

Trimethadione and Nephrosis