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PubMed1996

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.

Administration, Oral↗
PubMed1998

Trimethadione metabolism and microsomal monooxygenases in untreated and phenobarbital-treated rhesus monkeys.

The contribution of induced cytochrome P450 (P450) isozymes (CMLa; CYP2B, CMLb; CYP2A and CMLc; CYP3A) and related enzymes to trimethadione (TMO) metabolism in phenobarbital-treated rhesus monkey were investigated. The animals received a single dose of TMO (4 mg kg-1) and plasma samples were withdrawn before this administration and again at 0.08, 0.25, 0.5, 1 and 2 h later. Phenobarbital-treatment (20 mg kg-1 day-1 for 3 days; i.p.) significantly increased the plasma dimethadione (DMO)/TMO ratios at 0.08, 0.5, 1 and 2 h one's appropriate controls. Phenobarbital treatment also increased the P450 content (1.7-fold) and activity of aniline p-hydroxylase (1.3-fold), p-nitroanisole O-demethylase (1.8-fold) and benzphetamine N-demethylase (2.3-fold). The content of CMLa, CMLb and CMLc were increased about 12.8, 2.3 and 2.7-fold by phenobarbital pretreatment, respectively. The activity of TMO N-demethylation was inhibited by anti-P450 CMLa and anti-P450 CMLb. However, the anti-P450 CMLc antibody had no effect on this activity in liver microsomes. The results of both in vivo and in vitro studies of the effects of phenobarbital treatment on TMO metabolism indicate that these effects may be attributed to the induction of CMLa. These findings suggest that plasma DMO/TMO ratio in a single blood sampling after TMO administration is very useful for determination the degree of hepatic induction in clinical study.

Aniline Hydroxylase↗
PubMed2002

Embryonic arrhythmia by inhibition of HERG channels: a common hypoxia-related teratogenic mechanism for antiepileptic drugs?

PURPOSE: There is evidence that drug-induced embryonic arrhythmia initiates phenytoin (PHT) teratogenicity. The arrhythmia, which links to the potential of PHT to inhibit a specific potassium channel (Ikr), may result in episodes of embryonic ischemia and generation of reactive oxygen species (ROS) at reperfusion. This study sought to determine whether the proposed mechanism might be relevant for the teratogenic antiepileptic drug trimethadione (TMO). METHODS: Effects on embryonic heart rhythm during various stages of organogenesis were examined in CD-1 mice after maternal administration (125-1,000 mg/kg) of dimethadione (DMO), the pharmacologically active metabolite of TMO. Palatal development was examined after administration of a teratogenic dose of DMO and after simultaneous treatment with DMO and a ROS-capturing agent (alpha-phenyl-N-tert-butyl-nitrone; PBN). The Ikr blocking potentials of TMO and DMO were investigated in HERG-transfected cells by using voltage patch-clamping tests. RESULTS: DMO caused stage-specific (gestation days 9-13 only) and dose-dependent embryonic bradycardia and arrhythmia at clinically relevant maternal plasma concentrations (3-11 mM). Hemorrhage in the nasopharyngeal part of the embryonic palate (within 24 h) preceded cleft palate in fetuses at term. Simultaneous treatment with PBN significantly reduced the incidence of DMO-induced cleft palate, from 40 to 13%. Voltage patch-clamping studies showed that particularly DMO (70% inhibition), but also TMO, had Ikr blocking potential at clinically relevant concentrations. CONCLUSIONS: TMO teratogenicity, in the same way as previously shown for PHT, was associated with Ikr-mediated episodes of embryonic cardiac arrhythmia and hypoxia/reoxygenation damage.

Abnormalities, Drug-Induced↗
PubMed1987

Age-related changes in trimethadione oxidizing capacity.

The metabolism of trimethadione (TMO) following oral administration (4 mg kg-1) has been studied in 11 young male and 11 elderly male patients. The elimination half-life (h) of TMO was 11.8 +/- 1.4 (mean +/- s.e. mean) in the young and 23.5 +/- 2.17 in the elderly (P less than 0.01). Total body clearance (1 h-1 kg-1) was 41.4 +/- 2.8 in the young and 29.0 +/- 2.4 in the elderly (P less than 0.01). The apparent volume of distribution (1 kg-1) was 0.67 +/- 0.03 in the young and 0.65 +/- 0.04 in the elderly. Serum dimethadione (DMO)/TMO ratios at 4 h were 0.65 +/- 0.03 in the young and 0.46 +/- 0.03 in the elderly (P less than 0.01). These results suggest that N-demethylation of TMO is inversely related to age.

Adult↗
PubMedDate not supplied

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.

Animals↗
PubMed1979

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.

Abnormalities, Drug-Induced↗
PubMed1976

Intracellular pH of brain: alterations in acute respiratory acidosis and alkalosis.

To evaluate the metabolic adaptations of the brain to acute respiratory acid-base disturbances, a method was developed to measure intracellular pH (pHi) in the brain of dogs under conditions in which arterial pH is rapidly altered. Brain pHi was determined by measuring the distribution of 14C-labeled dimethadione (DMO) in brain relative to cortical CSF. Brain extracellular space (ECS) was evaluated as the 35SO4 = space relative to cortical CSF, and arterial Po2 was maintained at 82-110 mmHg. In normal dogs, brain (cerebral cortex) pHi was 7.05, and after 1 h of hypercapnia (arterial pH = 7.07) it fell to 6.93. However, after 3 h with arterial Pco2 maintained at 85 mmHg brain pHi was normal (7.06), and during this time brain bicarbonate had risen from 11.3 to 24.4 meq/kg H2O. These changes were not prevented by intravenous doses of acetazolamide,

Acid-Base Imbalance↗
PubMed1992

Maturational differences in acetazolamide-altered pH and HCO3 of choroid plexus, cerebrospinal fluid, and brain.

The carbonic anhydrase inhibitor acetazolamide is useful for analyzing ion transport, pH regulation, and fluid formation in developing central nervous system. We used the 14C-labeled dimethadione technique to measure alterations in steady-state pH, and to estimate the HCO3 concentration [HCO3], in choroid plexus (CP), cerebrospinal fluid (CSF), and cerebral cortex of 1- and 3-wk-old Sprague-Dawley rats treated with acetazolamide or probenecid. These drugs can suppress transport of HCO3 and other anions in some cells, consequently altering intracellular pH. In 1-wk-old infant rats whose CSF secretory process is incompletely developed, 1 h of acetazolamide treatment did not significantly change CP intracellular pH or [HCO3]. However, in 3-wk-old rats, in which the ability of CP to secrete ions and fluids is almost fully developed, acetazolamide caused marked increases in CP cell intracellular pH and [HCO3]. In contrast, acetazolamide-induced alkalinization was not observed in CSF or cerebral cortex of the 1- and 3-wk-old animals. The other test agent, probenecid (an inhibitor of anion transport but not of carbonic anhydrase), did not alter the pH of any region at any age investigated. Overall, the results are interpreted in light of developmental changes in carbonic anhydrase and previous findings from kinetic analyses of ion-translocating systems in CP. Acetazolamide may interfere with a CP apical membrane HCO3 extrusion mechanism not fully operational in infant rats.

Acetazolamide↗
PubMed1987

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.

Carcinoma, Hepatocellular↗
PubMed1989

The metabolism and excretion of trimethadione in patients with percutaneous transhepatic biliary drainage and renal dysfunction.

The metabolism and excretion of trimethadione (TMO) following an oral dose of 4 mg/kg has been examined in patients with percutaneous transhepatic biliary drainage (PTBD) and renal dysfunction. Biliary excretion as the total amount of TMO and its metabolite, dimethadione (DMO) was 2.0% of the dose during 0 to 48 h after TMO administration in patients with PTBD. Total urinary excretion (0-48 h) was 2.8% and 3.0% of the dose in healthy volunteers and patients with renal dysfunction, respectively. The serum DMO/TMO ratio at 4 h after oral dosing in patients of PTBD and renal dysfunction was not significantly changed in comparison with the ratio reported previously in healthy volunteers. The elimination half-life of TMO was also not altered in patients with PTBD in comparison with that reported previously in volunteers. These results suggest that metabolism and urinary and biliary excretion of TMO are not changed in patients with PTBD and renal dysfunction.

Adult↗
PubMed1984

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.

Adult↗
PubMed1986

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.

Adult↗
PubMed1986

Hepatic trimethadione-oxidizing capacity remains normal in patients with extrahepatic cholelithiasis.

In the present study, using trimethadione (TMO) as an indicator substrate, we estimated pre- and post-operative differences in hepatic drug-oxidizing capacity in patients with extrahepatic cholelithiasis. Only total and direct bilirubin values were significantly higher in preoperative patients than in the controls. After operative procedures, those parameters did not show significant differences from corresponding control values. The serum dimethadione (DMO)/TMO ratios estimated 4 h after administration of 4 mg/kg of TMO. Neither pre- nor post-operative serum DMO/TMO ratios were significantly different from those in the controls. These results suggest that the hepatic drug-oxidizing capacity in patients with extrahepatic cholelithiasis remains unchanged even though the bilirubin level deviated from normal.

Bilirubin↗
PubMed1986

Influence of short-term water deprivation on kinetics of trimethadione and its metabolite in rats.

The effects of acute (24-, 48- or 72-hr) water deprivation on the disposition kinetics of trimethadione (TMO) and its only metabolite, dimethadione (DMO), and on the microsomal hepatic drug-oxidizing enzyme activities were investigated in male rats. The DMO/TMO ratios in the serum at 2 hr after intravenous administration of 100 mg/kg TMO were significantly decreased in 48- and 72-hr water-deprived rats, but in 24-hr water-deprived rats, the DMO/TMO ratios were not changed as compared to controls and food restrictions. In the 48- and 72-hr water-deprived rats, contents of cytochrome p-450 and activities of aminopyrine N-demethylase were significantly decreased. On the other hand, activities of aniline hydroxylase in these rats were significantly increased as compared to controls and food restrictions. These results suggest that the effects of water deprivation on drug metabolism not only depend on the time of water deprivation but also vary with the indicator substrate.

Aminopyrine N-Demethylase↗
PubMed1995

Influence of partial hepatectomy in dogs on trimethadione metabolism and microsomal monooxygenases.

1. The recovery of trimethadione (TMO) metabolism and its association with liver weight and the activity of TMO N-demethylase have been reported in rat following partial (68%) hepatectomy. In the present study, we examined the effect of liver regeneration on hepatic P450 isozymes and TMO metabolism in dog. 2. The ratio of dimethadione (DMO), being the only TMO metabolite, to TMO at 2 h after i.v. injection of TMO (4 mg/kg) fell to 80% of that in the preoperative animals by 24 h after hepatectomy. The DMO/TMO ratio gradually recovered from days 7 to 14, and by day 21 after hepatectomy it had increased to about 25%. At 28 days post-hepatectomy the ratio had returned to preoperative levels. 3. The activity of benzphetamine N-demethylase, TMO N-demethylase, p-nitro-anisole O-demethylase and aniline hydroxylase increased 3 days post-hepatectomy, exhibiting levels 4.77, 3.45, 1.51 and 1.91 times greater respectively than that of the preoperative liver in the same animal. Two weeks post-hepatectomy these activities had returned to normal. The activity of the 16 beta- and 2 beta-hydroxylation of testosterone was unchanged. However, the activity of 6 beta-hydroxylase decreased 7 days post-hepatectomy, while 16 alpha-hydroxylation had increased at 3 and 7 days post-hepatectomy compared with controls. 4. The changes in liver weight were nearly restored to preoperative levels 7 days post-hepatectomy. 5. Although the P450 content was unchanged from days 1 to 7 post-hepatectomy, it had decreased by 30% at day 14 and by 20% at day 28. The P4502B11 content 3, 7 and 14 days post-hepatectomy had increased 8, 10 and 2 times respectively, while the P4503A12 content at 7 and 14 days decreased by 30 approximately 50% compared with that of the pre-operative liver. 6. The data presented above do not reveal any relationship between P4502B11 induction and liver regeneration. The reason for such a change is unknown, therefore further investigation needs to be carried out.

Animals↗
PubMed2003

Disruption of bovine oocytes and preimplantation embryos by urea and acidic pH.

Feeding cattle diets high in degradable crude protein (CP) or in excess of requirements can reduce fertility and lower uterine pH. Objectives were to determine direct effects of urea and acidic pH during oocyte maturation and embryonic development. For experiment 1, oocytes were matured in medium containing 0, 5, 7.5, or 10 mM urea (0, 14, 21, or 28 mg/dl urea nitrogen, respectively). Cleavage rate was not reduced by any concentration of urea. However, the proportion of oocytes developing to the blastocyst stage at d 8 after insemination was reduced by 7.5 mM urea. In addition, the proportion of cleaved oocytes becoming blastocysts was decreased by 5 and 7.5 mM urea. For experiment 2, putative zygotes were collected -9 h after insemination and cultured in modified Potassium Simplex Optimized Medium (KSOM). Urea did not reduce the proportion of oocytes developing to the blastocyst stage, although 10 mM urea reduced cleavage rate slightly. For experiment 3, dimethadione (DMD), a weak nonmetabolizable acid, was used to decrease culture medium pH. Putative zygotes were cultured in modified KSOM containing 0, 10, 15, or 20 mM DMD for 8 d. DMD reduced cleavage rate at 15 and 20 mM and development to the blastocyst stage at all concentrations. Results support the idea that feeding diets rich in highly degradable CP compromises fertility through direct actions of urea on the oocyte and through diet-induced alterations in uterine pH.

Animals↗
PubMed1987

[Measurement of microsomal function in hepatectomized rat].

Trimethadione (TMO) is exclusively metabolized to dimethadione (DMO) by cytochrome P-450 dependent mono-oxygenase in liver microsomes. We have chosen TMO as an indicator compound for estimating the microsomal function of the liver. TMO tolerance test was performed in the CCl4 intoxicated injury or 68% partial-hepatectomized rats. Serum DMO/TMO ratios in 2 hours following oral administration of TMO in these rats in vivo were well correlated with changes in content of hepatic cytochrome P-450 and activity of TMO N-demethylase in vitro. TMO tolerance test could also determine quantitatively the changes of the functional capacity of the liver in the 68% partial hepatectomy. These results suggest that TMO tolerance test is a useful tool for the surgical indication in the hepatectomy.

Animals↗
PubMed1977

Evaluation of anticonvulsants in barbiturate withdrawal.

Four prototypic anticonvulsants were tested for their effectiveness against barbiturate withdrawal in cats. The effects were evaluated on a total of over 20 motor, autonomic and behavioral withdrawal signs. The animals were made physically dependent by 5 weeks of twice daily "maximally tolerable" sodium pentobarbital dosing intragastrically. Anticonvulsants were administered by intravenous infusion 25 hours after the final dose of chronic pentobarbital treatment when all withdrawal signs had become severe and grand mal type withdrawal convulsions were observed. Phenobarbital blocked withdrawal signs quite effectively at doses that caused no significant acute central nervous system depression. Trimethadione also reversed most withdrawal signs, but some signs persisted even at doses causing overt acute toxicity. Dimethadione was less effective than the parent compound, trimethadione, in reversing withdrawal but caused greater acute toxicity. Phenytoin was in effective for most withdrawal signs and some signs were made worse. The clonic phase of withdrawal convulsions was accentuated and the overall condition of the animals worsened. During withdrawal, the animals were less sensitive (tolerant) to phenobarbital but were more sensitive to acute toxicity from the other drugs tested.

Animals↗