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Einosuke Tanaka - One of the best experts on this subject based on the ideXlab platform.
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Trimethadione metabolism and microsomal monooxygenases in untreated and phenobarbital treated rhesus monkeys
Comparative Biochemistry and Physiology Part C: Pharmacology Toxicology and Endocrinology, 1998Co-Authors: Einosuke Tanaka, Tomoyoshi Taniguchi, Yoshio Sawa, Shigeru Ohmori, Mitsukazu Kitada, Tohoru HorieAbstract: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 The animals received a single dose of TMO (4 mg kg-1) and plasma samples were withdrawn before this administration and again at 0.08, 0.25, 0.5, 1 and 2 h later.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.
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simultaneous determination of Trimethadione and its metabolite in rat and human serum by high performance liquid chromatography
Journal of Chromatography A, 1998Co-Authors: Einosuke Tanaka, Takemi Yoshida, Shigenobu Hagino, Yukio KuroiwaAbstract:Abstract 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.
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Trimethadione metabolism and assessment of hepatic drug oxidizing capacity
Methods in Enzymology, 1996Co-Authors: Einosuke Tanaka, Yoshihiko FunaeAbstract:Publisher Summary This chapter discusses the metabolism and assessment of hepatic drug-oxidizing capacity using Trimethadione. Measurement of the activity of drug-metabolizing enzymes of the liver, which largely depends on cytochrome P450, is essential in evaluating the capacity of oxidative drug metabolism in liver disease. Trimethadione (TMO), an antiepileptic drug, may be a more suitable candidate for estimating hepatic drug-oxidizing activity. It is rapidly absorbed from the gastrointestinal tract, distributed into total body fluids, and is extensively N-demethylated to dimethadione (DMO) by P450-dependent monooxygenases in liver microsomes. The pharmacokinetic properties of TMO enable the determination of hepatic microsomal function with a single blood sample. The chapter discusses that the TMO may be used as a probe drug for the rapid determination of the hepatic drug-oxidizing capacity and the functional reserve mass of the liver.
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pharmacokinetics of tacrolimus and Trimethadione after canine liver transplantation
The Japanese Journal of Gastroenterological Surgery, 1996Co-Authors: M Otsuka, Akio Ishikawa, Katashi Fukao, Kenji Yuzawa, Hiroyuki Iida, Tadashi Kondo, Shinya Adachi, Takeshi Todoroki, Einosuke TanakaAbstract:肝移植に伴う肝阻血障害が移植肝ミクロソーム機能におよぼす影響について, タクロリムスとトリメタジオン (TMO) の薬物動態により検討した. 雑種成犬を用いた同所性全肝移植後第1日と第7日に, タクロリムスとTMOの薬物動態を調べ, 無処置犬を対照群として比較した. タクロリムスは0.3mg/kgを30分かけて静注し, 全血中濃度の変化を測定した. TMOは4mg/kgを急速静注し, 血清中のTMOとその代謝物であるジメタジオン (DMO) の変化を測定した. 両群とも薬物動態を調べる日以外はタクロリムス0.3mg/kg/日を経口的に投与した. TMOのクリアランスと投与2時間後の血清中DMO/TMO比は, 肝移植群で移植後第1日に低下していたが第7日には両群間に差を認めなかった. タクロリムスのクリアランス, 投与24時間後の血中濃度は移植後第1日, 第7日とも両群間に差を認めなかった. TMOの代謝はタクロリムスの代謝に比べて肝阻血による障害を強くうけることが示された.
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correlation between Trimethadione tolerance test and morphometric pathological parameters in chronic liver diseases
Kanzo, 1996Co-Authors: Katsuhisa Tsuji, Akio Ishikawa, Akira Osada, Katashi Fukao, Mikio Doi, Yuuji Yamamoto, Mitsuhiro Matsuda, Masaaki Ohtsuka, Ken Todoroki, Einosuke TanakaAbstract:肝ミクロゾーム分画で代謝される抗てんかん薬のTrimethadione (TMO)を用いた負荷試験が,肝のいかなる組織形態学所見を反映しているか検討した.対象は肝硬変(LC) 16例,慢性肝炎(CH)と肝線維症の各2例の20例である.術前の肝CT像より算出した肝容積と肝組織の光学顕微鏡所見の画像解析により肝実質比(実質/実質+間質)や単位体積あたりの細胞数を求めた.それらの指標より肝実質量(肝容積×実質比),肝細胞量(肝容積×単位体積あたりの肝細胞数),肝実質細胞総量(肝容積×実質比×単位体積あたりの細胞数)を算出した.TMO負荷試験値と肝実質量や肝細胞量とは,それぞれ高い相関(r=0.771, r=0.809; p<0.0001)を認め,さらに肝細胞数を最も反映すると思われる肝実質細胞総量とも高い相関を認めた(r=0.798, p<0.0001).以上よりTMO負荷試験が肝のfunctional volumeを評価できるのは肝細胞数をよく反映しているためと考えられた.
Akio Ishikawa - One of the best experts on this subject based on the ideXlab platform.
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pharmacokinetics of tacrolimus and Trimethadione after canine liver transplantation
The Japanese Journal of Gastroenterological Surgery, 1996Co-Authors: M Otsuka, Akio Ishikawa, Katashi Fukao, Kenji Yuzawa, Hiroyuki Iida, Tadashi Kondo, Shinya Adachi, Takeshi Todoroki, Einosuke TanakaAbstract:肝移植に伴う肝阻血障害が移植肝ミクロソーム機能におよぼす影響について, タクロリムスとトリメタジオン (TMO) の薬物動態により検討した. 雑種成犬を用いた同所性全肝移植後第1日と第7日に, タクロリムスとTMOの薬物動態を調べ, 無処置犬を対照群として比較した. タクロリムスは0.3mg/kgを30分かけて静注し, 全血中濃度の変化を測定した. TMOは4mg/kgを急速静注し, 血清中のTMOとその代謝物であるジメタジオン (DMO) の変化を測定した. 両群とも薬物動態を調べる日以外はタクロリムス0.3mg/kg/日を経口的に投与した. TMOのクリアランスと投与2時間後の血清中DMO/TMO比は, 肝移植群で移植後第1日に低下していたが第7日には両群間に差を認めなかった. タクロリムスのクリアランス, 投与24時間後の血中濃度は移植後第1日, 第7日とも両群間に差を認めなかった. TMOの代謝はタクロリムスの代謝に比べて肝阻血による障害を強くうけることが示された.
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correlation between Trimethadione tolerance test and morphometric pathological parameters in chronic liver diseases
Kanzo, 1996Co-Authors: Katsuhisa Tsuji, Akio Ishikawa, Akira Osada, Katashi Fukao, Mikio Doi, Yuuji Yamamoto, Mitsuhiro Matsuda, Masaaki Ohtsuka, Ken Todoroki, Einosuke TanakaAbstract:肝ミクロゾーム分画で代謝される抗てんかん薬のTrimethadione (TMO)を用いた負荷試験が,肝のいかなる組織形態学所見を反映しているか検討した.対象は肝硬変(LC) 16例,慢性肝炎(CH)と肝線維症の各2例の20例である.術前の肝CT像より算出した肝容積と肝組織の光学顕微鏡所見の画像解析により肝実質比(実質/実質+間質)や単位体積あたりの細胞数を求めた.それらの指標より肝実質量(肝容積×実質比),肝細胞量(肝容積×単位体積あたりの肝細胞数),肝実質細胞総量(肝容積×実質比×単位体積あたりの細胞数)を算出した.TMO負荷試験値と肝実質量や肝細胞量とは,それぞれ高い相関(r=0.771, r=0.809; p<0.0001)を認め,さらに肝細胞数を最も反映すると思われる肝実質細胞総量とも高い相関を認めた(r=0.798, p<0.0001).以上よりTMO負荷試験が肝のfunctional volumeを評価できるのは肝細胞数をよく反映しているためと考えられた.
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influence of partial hepatectomy in dogs on Trimethadione metabolism and microsomal monooxygenases
Xenobiotica, 1995Co-Authors: Einosuke Tanaka, Akio Ishikawa, T Nakamura, A Osada, Y Momose, T Mikami, K Fukao, Toru HorieAbstract: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 (4mg/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...
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changes in caffeine lidocaine and Trimethadione metabolism in carbon tetrachloride intoxicated rats as assessed by a cocktail study
Pharmacology & Toxicology, 1994Co-Authors: Einosuke Tanaka, Akio Ishikawa, Shogo MisawaAbstract:: We investigated the possibility of predicting liver damage from changes in the serum concentrations of caffeine (10 mg/kg), lidocaine (4 mg/kg) and Trimethadione (4 mg/kg), which are metabolized catalysed by different cytochrome P450 (P450) and/or are dependent on blood flow, in rats with carbon tetrachloride (CCl4: 0.25 ml/kg)-induced liver injury using a strategy referred to as a “cocktail” study. These 3 probe drugs were simultaneously administered intravenously. The half-lives (t1/2) of caffeine, lidocaine and Trimethadione were significantly longer in the CCl4-treated group than in oil-treated controls, but no significant differences were observed in mean apparent volumes of distribution (Vd). Serum total body clearance (CL) values of all three drugs were markedly reduced in CCl4-treated animals. In rats with liver damage, the production of 3 metabolites (theobromine, paraxanthine and theophylline) of caffeine in addition to the only metabolite (dimethadione) of Trimethadione after intravenous administration of probe drugs were significantly reduced compared to those of controls. These findings suggest that each probe drug, metabolized by different or partially overlapping P450, is useful in evaluating drug-oxidizing capacity in liver disease.
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Trimethadione metabolism as a probe drug to estimate hepatic oxidizing capacity in rats
Comparative Biochemistry and Physiology Part C: Comparative Pharmacology, 1993Co-Authors: Einosuke Tanaka, Shinichi Kobayashi, Akio Ishikawa, Shogo Misawa, Hajime Yasuhara, Yukio KuroiwaAbstract: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.
H Yasuhara - One of the best experts on this subject based on the ideXlab platform.
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Trimethadione metabolism by human liver cytochrome p450 evidence for the involvement of cyp2e1
Xenobiotica, 1998Co-Authors: Norimitsu Kurata, Yuki Nishimura, Mariko Iwase, N E Fischer, B K Tang, T Inaba, H YasuharaAbstract:1. Caucasian liver samples were used in this study. N-demethylation of Trimethadione (TMO) to dimethadione (DMO) was monitored in the presence of chemical inhibitors of CYPs, such as fluconazole, quinidine, dimethyl-nitrosamine, acetaminophen, phenacetin, chlorzoxazone and mephenytoin. Trimethadione N-demethylation was selectively inhibited by dimethylnitrosamine and chlorzoxazone (> 50%) and weakly inhibited by tolbutamide (12%) and fluconazole (22%), whereas other inhibitors showed no effect. This result suggested that TMO metabolism to DMO is mainly mediated by CYP2E1 and marginally by CYP2C and CYP3A4. 2. Fifteen human livers were screened and interindividual variability of TMO N-demethylation activity was 3-fold. Chlorzoxazone 6-hydroxylation activity was also measured and both activities were significantly correlated (r=0.735, p < 0.01). 3. DMO production by human cDNA expressed CYP enzymes was observed mainly for CYP2E1 (10.8 nmol/tube), marginally for CYP2C8 (0.22 nmol tube) and not detectable for...
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Trimethadione n demethylation by rat liver cyp2e1 in vitro
Research Communications in Molecular Pathology and Pharmacology, 1996Co-Authors: Yuki Nishimura, Eiji Uchida, N Kurata, M Watanabe, H YasuharaAbstract:Trimethadione (TMO) is a model drug utilized for estimation of hepatic metabolism in clinical studies, and it was reported that TMO N-demethylase activity was inhibited by CYP2E1 inhibitors and substrates in rat in vivo. This study was performed to investigate the involvement of the CYP2E1 subfamily on TMO N-demethylation in vitro and to clarify these inhibitory mechanisms. The effects of acetone (AC), imidazole (IM) and N-nitrosodimethylamine (NDA) on TMO N-demethylation were studied in vitro. Rat hepatic microsomal fractions were employed as the enzyme source of TMO N-demethylase and the activity was determined by the production of dimethadione (DMO). DMO was analyzed by a GC/FTD equipped with a narrow-bore capillary column. TMO N-demethylation was biphasic by the graphic analysis of Eadie-Hofstee plots; this suggests the involvement of at least two enzymes in TMO metabolism in the rat. The kinetic parameters for the formation of DMO were analyzed graphically using double-reciprocal plots. The apparent K(m1), K(m2) and Vmax1, Vmax2 values for DMO formation were 4, 20 mM and 182, 595 pmol/mg protein/min, respectively. AC and IM inhibited TMO N-demethylase activity competetively. However, mixed inhibition kinetics was observed by NDA. Furthermore, TMO N-demethylase activity was inhibited by antiserum to CYP2E1 by 62% and CYP3A2 by 46%. These results indicate that the CYP2E1 subfamily is the major enzyme involved in TMO N-demethylation in rat in vitro although the CYP3A2 is also involved in this transformation.
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the effects of inhibitors and substrates of different types of cytochrome p450 isozymes on serum dimethadione Trimethadione ratio in rats in vivo
Research Communications in Molecular Pathology and Pharmacology, 1995Co-Authors: Yuki Nishimura, Eiji Uchida, N Kurata, S Kobayashi, H YasuharaAbstract:Trimethadione(TMO) is regarded as a model drug for estimating the hepatic drug oxidative capacity in vivo. However, the P450 isozymes that are responsible for TMO N-demethylation have not been identified clearly yet. This study was designed to determine these P450 isozymes that participate in the TMO N-demethylation in vivo by employing several typical P450 inhibitors and substrates. Male Sprague-Dawley(SD) rats were pretreated with P450 inhibitors or substrates before TMO(100mg/kg, p.o.) treatment. Serum dimethadione(DMO)/TMO ratios were employed for the assessment of metabolic capacity toward TMO. Pretreatment with imidazole and acetone significantly decreased the DMO/TMO ratios in a dose related manner. Weaker inhibitory effects were observed with SKF525A. However, pretreatment with alpha-naphthoflavone, quinine, debrisoquine, triacetyloleandomycin and lauric acid did not affect the ratios. These results suggest that various forms of P450 are involved in TMO metabolism to some extent and that CYP2E1 is attributed to major P450 isozyme for TMO N-demethylation in vivo.
Yoshihiko Funae - One of the best experts on this subject based on the ideXlab platform.
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Trimethadione metabolism and assessment of hepatic drug oxidizing capacity
Methods in Enzymology, 1996Co-Authors: Einosuke Tanaka, Yoshihiko FunaeAbstract:Publisher Summary This chapter discusses the metabolism and assessment of hepatic drug-oxidizing capacity using Trimethadione. Measurement of the activity of drug-metabolizing enzymes of the liver, which largely depends on cytochrome P450, is essential in evaluating the capacity of oxidative drug metabolism in liver disease. Trimethadione (TMO), an antiepileptic drug, may be a more suitable candidate for estimating hepatic drug-oxidizing activity. It is rapidly absorbed from the gastrointestinal tract, distributed into total body fluids, and is extensively N-demethylated to dimethadione (DMO) by P450-dependent monooxygenases in liver microsomes. The pharmacokinetic properties of TMO enable the determination of hepatic microsomal function with a single blood sample. The chapter discusses that the TMO may be used as a probe drug for the rapid determination of the hepatic drug-oxidizing capacity and the functional reserve mass of the liver.
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Trimethadione metabolism a useful indicator for assessing hepatic drug oxidizing capacity
Biochemical Pharmacology, 1994Co-Authors: Mayumi Nakamura, Einosuke Tanaka, Shogo Misawa, Tsutomu Shimada, Susumu Imaoka, Yoshihiko FunaeAbstract:Abstract The metabolism of Trimethadione (TMO), a useful indicator of hepatic drug-oxidizing capacity in rats and humans, was studied using 14 different forms of rat cytochrome P450 (CYP1A1,1A2, 2A1, 2A2,2B1,2B2,2C6,2C7, 2C11,2C12,2C13,2E1,3A2 and 4A2) and three forms of human cytochrome P450 (CYP1A2,2C and 3A4). TMO N-demethylation was increased by treating rats with phenobarbital. CYP2C11 and 2B1 had high TMO N-demethylase activity, but 1A1 and 1A2 had low activity. Antibodies raised to CYP2C11 and 2B1/2 inhibited TMO N-demethylation in hepatic microsomes of untreated and phenobarbital-treated rats, respectively. In a reconstituted system, human CYP3A4 and 2C produced efficiently dimethadione (DMO), but CYP1A2 did not catalyse TMO N-demethylation. Antibodies raised to CYP3A2 and 2C11 inhibited TMO N-demethylation in human hepatic microsomes. These results indicated that the N-demethylation of TMO is catalysed mainly by CYP2C11 and 2B1 in rat hepatic microsomes, and that human CYP3A4 and an unspecified isoform of the 2C subfamilies contribute to TMO N-demethylation in human liver.
Shogo Misawa - One of the best experts on this subject based on the ideXlab platform.
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changes in caffeine lidocaine and Trimethadione metabolism in carbon tetrachloride intoxicated rats as assessed by a cocktail study
Pharmacology & Toxicology, 1994Co-Authors: Einosuke Tanaka, Akio Ishikawa, Shogo MisawaAbstract:: We investigated the possibility of predicting liver damage from changes in the serum concentrations of caffeine (10 mg/kg), lidocaine (4 mg/kg) and Trimethadione (4 mg/kg), which are metabolized catalysed by different cytochrome P450 (P450) and/or are dependent on blood flow, in rats with carbon tetrachloride (CCl4: 0.25 ml/kg)-induced liver injury using a strategy referred to as a “cocktail” study. These 3 probe drugs were simultaneously administered intravenously. The half-lives (t1/2) of caffeine, lidocaine and Trimethadione were significantly longer in the CCl4-treated group than in oil-treated controls, but no significant differences were observed in mean apparent volumes of distribution (Vd). Serum total body clearance (CL) values of all three drugs were markedly reduced in CCl4-treated animals. In rats with liver damage, the production of 3 metabolites (theobromine, paraxanthine and theophylline) of caffeine in addition to the only metabolite (dimethadione) of Trimethadione after intravenous administration of probe drugs were significantly reduced compared to those of controls. These findings suggest that each probe drug, metabolized by different or partially overlapping P450, is useful in evaluating drug-oxidizing capacity in liver disease.
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Trimethadione metabolism a useful indicator for assessing hepatic drug oxidizing capacity
Biochemical Pharmacology, 1994Co-Authors: Mayumi Nakamura, Einosuke Tanaka, Shogo Misawa, Tsutomu Shimada, Susumu Imaoka, Yoshihiko FunaeAbstract:Abstract The metabolism of Trimethadione (TMO), a useful indicator of hepatic drug-oxidizing capacity in rats and humans, was studied using 14 different forms of rat cytochrome P450 (CYP1A1,1A2, 2A1, 2A2,2B1,2B2,2C6,2C7, 2C11,2C12,2C13,2E1,3A2 and 4A2) and three forms of human cytochrome P450 (CYP1A2,2C and 3A4). TMO N-demethylation was increased by treating rats with phenobarbital. CYP2C11 and 2B1 had high TMO N-demethylase activity, but 1A1 and 1A2 had low activity. Antibodies raised to CYP2C11 and 2B1/2 inhibited TMO N-demethylation in hepatic microsomes of untreated and phenobarbital-treated rats, respectively. In a reconstituted system, human CYP3A4 and 2C produced efficiently dimethadione (DMO), but CYP1A2 did not catalyse TMO N-demethylation. Antibodies raised to CYP3A2 and 2C11 inhibited TMO N-demethylation in human hepatic microsomes. These results indicated that the N-demethylation of TMO is catalysed mainly by CYP2C11 and 2B1 in rat hepatic microsomes, and that human CYP3A4 and an unspecified isoform of the 2C subfamilies contribute to TMO N-demethylation in human liver.
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Trimethadione metabolism as a probe drug to estimate hepatic oxidizing capacity in rats
Comparative Biochemistry and Physiology Part C: Comparative Pharmacology, 1993Co-Authors: Einosuke Tanaka, Shinichi Kobayashi, Akio Ishikawa, Shogo Misawa, Hajime Yasuhara, Yukio KuroiwaAbstract: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.
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improved method for the determination of Trimethadione and its demethylated metabolite dimethadione in human serum by gas chromatography
Journal of Chromatography B: Biomedical Sciences and Applications, 1992Co-Authors: Einosuke Tanaka, Shogo MisawaAbstract:An improved gas chromatographic method, involving the use of a wide-bore capillary column, for the determination of Trimethadione and its only demethylated metabolite, dimethadione, in human serum is described. The results indicate that both substances and the internal standard (maleinimide) were well separated with no tailing peak. The detection limit was 10 ng/ml for Trimethadione and 50 ng/ml for dimethadione. This improved method is reliable in terms of sensitivity, selectivity and reproducibility for the simultaneous determination of both compounds in human serum.
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simplified test for determination of drug oxidizing capacity in rats with chemical induced liver injury using caffeine and Trimethadione as model drugs
Pharmacology & Toxicology, 1992Co-Authors: Einosuke Tanaka, Akio Ishikawa, Shogo MisawaAbstract:: We examined the possibility of predicting the extent of hepatic drug-oxidizing capacity by determination of caffeine, Trimethadione and their metabolites in three groups of rats with chemically induced liver injuries. Trimethadione (4 mg/kg) and caffeine (10 mg/kg) were simultaneously administered as two probe drugs. In rats with chemically induced liver injuries pretreated with carbon tetrachloride (CCl4: 0.25 ml/kg), α-naphthylisothiocyanate (ANIT: 40 mg/kg), or D-galactosamine (GalN: 400 mg/kg), the half-life (t1/2) of caffeine and Trimethadione was significantly (P < 0.01) prolonged compared to those of control groups total body clearance as dramatically reduced (P < 0.01), whereas apparent volumes of distribution (Vds) were increased in ANIT and GalN groups. In rats with liver damage the production of three metabolites (theobromine, paraxanthine and theophylline) of caffeine as well as the only metabolite (dimethadione) of Trimethadione after oral administration of both drugs were significantly decreased compared to those of controls. In rats with liver injuries, total body clearance of caffeine and Trimethadione showed a strong correlations (r = 0.99, P < 0.01); also total body clearance of caffeine correlated well with the ratio of dimethadione/Trimethadione after 1, 2, and 4 hr of Trimethadione administration (r = 0.93, P < 0.01; r = 0.97, P < 0.01 and r = 0.97, P < 0.01 respectively). Besides, total body clearance of caffeine also correlated well (coefficients ranging from 0.74 to 0.96; P < 0.01) with the ratio of theobromine/ caffeine, paraxanthine/caffeine and theophylline/caffeine after 1, 2 and 4 hr) of caffeine administration. These findings indicate that the hepatic drug-oxidizing capacity can be evaluated by measuring the plasma concentration ratios of caffeine or Trimethadione to their metabolites using single blood sampling within a short time (1 or 2 hr) after administration of caffeine or Trimethadione to rats with chemically induced liver injuries.
