Toxicokintic and toxicodynamic analysis of clofibrate based on free drug concentrations in nagase analbuminemia rats (NAR)
スポンサーリンク
概要
- 論文の詳細を見る
Toxicokinetics (TK) is usually performed by measurement of the total drug concentrations in plasma. However, free drug concentrations in plasma are considered to correlate directly with toxicodynamics (TD). In the present study, to evaluate the applicability of TK/TD analysis based on free drug concentrations, we investigated the TK/TD of clofibrate, which binds to albumin with a higher ratio, using an albumin-deficient mutant strain, Nagase analbuminemia rats (NAR). TK, blood chemistry, histopathology, drug and fatty acid metabolizing enzymes and microarray analysis in the liver were examined after a 4-day oral administration of clofibrate. Compared to Sprague-Dawley (SD) rats, the parent strain of NAR, 4.1-fold higher AUC_<0-24hr> based on free drug concentrations (3445 versus 844 μg・hr/ml) was observed in NAR when both rats showed the same level of AUC_<0-24>hr based on the total drug concentrations (4436 versus 4237μg・hr/ml). Additionally, more severe hepatocellular hypertrophy, increase in aspartate transaminase (AST), alanine aminotransferase (ALT) and lactate dehydrogenase (LDH), decrease in total cholesterol (T.CHO), phospholipid (PL), triglyceride (TG), and non-esterified fatty acid (NEFA), and increase in the mRNA levels of fatty acid metabolizing enzymes (FAOS, CAT, and CPT) were observed in NAR at the same dose. These results demonstrated that NAR developed more severe toxicities and pharmacological effects than SD rats correlating with the higher AUC of the free drug concentrations. The results also suggested that TK/TD analysis based on the free drug concentration is appropriate to interpret the relationship between exposure and toxicity in cases of protein binding saturation including protein decrease or species differences on protein binding, especially when drugs showing a higher protein binding ratio are dosed.
- 2008-08-01
著者
-
UENO Koichi
Department of Geriatric Pharmacology and Therapeutics, Graduate School of Pharmaceutical Sciences, C
-
Takasaki Wataru
Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd.
-
Manabe Sunao
Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd.
-
KIYOSAWA Naoki
Medical Safety Research Labs., Sankyo Co., Ltd.
-
WATANABE Kyoko
Medical Safety Research Labs., Sankyo Co., Ltd.
-
HONDA Kumi
Medicinal Safety Research Labs., Sankyo Co., Ltd.
-
ARAKAWA Shingo
Medicinal Safety Research Laboratories, Sankyo, Co., Ltd.
-
SHIBAYA Yukari
Medicinal Safety Research Laboratories, Sankyo, Co., Ltd.
-
真鍋 淳
Medicinal Safety Research Laboratories Daiichi-sankyo Co. Ltd.
-
真鍋 淳
三共
-
真鍋 淳
Laboratory Animal Science And Toxicology Laboratories Sankyo Co. Ltd.
-
Miida Hiroaki
Department of Geriatric Pharmacology and Therapeutics, Graduate School of Pharmaceutical Sciences, C
-
Manabe Sunao
Medicinal Safety Research Laboratories Daiichi Sankyo Co. Ltd.
-
Honda Kumi
Medicinal Safety Research Labs. Daiichi Sankyo Co. Ltd.
-
Ueno Koichi
Department Of Geriatric Pharmacology And Therapeutics Graduate School Of Pharmaceutical Sciences Chi
-
Manabe Sunao
Medical Safety Research Laboratories Sankyo Co. Ltd.
-
Kiyosawa Naoki
Toxicogenomics Project National Inst. Of Biomedical Innovation
-
Kiyosawa Naoki
Medical Safety Research Laboratories Sankyo Co. Ltd.
-
Kiyosawa Naoki
Dpt. Of Veterinary Pathology Graduate School Of Agricultural And Life Sciences The University Of Tok
-
Arakawa Shingo
Medicinal Safety Research Laboratories Daiichi Sankyo Co. Ltd.
-
Watanabe Kyoko
Medicinal Safety Research Labs. Daiichi Sankyo Co. Ltd.
-
Miida Hiroaki
Department Of Geriatric Pharmacology And Therapeutics Graduate School Of Pharmaceutical Sciences Chi
-
Manabe Sunao
Med.safe.res.labs. Sankyo Co. Ltd. Of Shizuoka Pref.
-
Manabe Sunao
Lab. Anim. Sci. & Toxicol. Lab. Sankyo Co. Ltd.
-
Takasaki Wataru
Medicinal Safety Laboratories Daiichi Sankyo Co. Ltd.
-
Takasaki Wataru
Medicinal Safety Research Labs. Daiichi Sankyo Co. Ltd.
-
Takasaki Wataru
Analytical And Metabolic Research Laboratories Sankyo Co. Ltd.
-
Takasaki Wataru
Pharmaceutical Institute Tohoku University
-
Shibaya Yukari
Medicinal Safety Research Labs. Daiichi Sankyo Co. Ltd.
-
Ueno Koichi
Department Of Drug Evaluation And Toxicological Sciences Faculty Of Pharmaceutical Sciences Chiba Un
-
Takasaki W
Medicinal Safety Research Labs. Daiichi Sankyo Co. Ltd.
-
Manabe Sunao
Medicinal Safety Research Labs. Daiichi Sankyo Co. Ltd.
-
Kiyosawa Naoki
Medicinal Safety Research Labs. Daiichi Sankyo Co. Ltd.
-
Honda Kumi
Medicinal Safety Research Labs. Sankyo Co. Ltd.
-
UENO Koichi
Department of Biochemical Pharmacology and Biotoxicology, Faculty of Pharmaceutical Sciences, Chiba University
関連論文
- Expression of histamine H4 receptor in human epidermal tissues and attenuation of experimental pruritus using H4 receptor antagonist
- The structure-activity relationship between oxycoumarin derivatives showing inhibitory effects on iNOS in mouse macrophage RAW264.7 cells
- Retroperitoneal Fibromatosis in a Cynomolgus Monkey (Macaca fascicularis)
- Toxicokintic and toxicodynamic analysis of clofibrate based on free drug concentrations in nagase analbuminemia rats (NAR)
- Enhanced Effect of Connexin 43 on Cisplatin-Induced Cytotoxicity in Mesothelioma Cells
- An Attempt to Predict the Response of Human Glutathione S-Transferase (GST) to Chemical Inducers Using Transgenic Rats Harboring Human GST Gene
- Different responses in mutagenesis induced by quinolone antibacterial agents in two Escherichia coli WP2uvrA/pKM101 strains
- Effect of glutathione (GSH) depletion on DNA damage and blood chemistry in aged and young rats
- Thirteen-week Intravenous Toxicity Study of a Novel Humanized Anti-Human Death Receptor 5 Monoclonal Antibody, CS-1008, in Cynomolgus Monkeys
- CHARACTERIZATION OF RESISTANCE TO BROMOBENZENE-INDUCED HEPATOTOXICITY BY MICROARRAY
- RESISTANCE TO THE SKELETAL MUSCLE INJURY EXPRESSED BY REPEATED TREATMENT WITH COMPOUND A THAT HAS HMG-CoA REDUCTASE INHIBITORY ACTIVITY
- P7-41 Skeletal muscle injury caused by compound A completely recovers in spite of further treatment?(GENERAL TOXICITY)(GENERAL SESSION BY POSTER PRESENTATION)(Proceedings of the 31st Annual Meeting)
- A NOVEL MODEL OF CONTINUOUS DEPLETION OF GLUTATHIONE IN MICE TREATED WITH L-BUTHIONINE (S,R)-SULFOXIMINE
- Involvement of Drug Transporters in the Acquired Resistance to Bromobenzene-induced Hepatotoxicity (LIVER/DIGESTIVE SYSTEM) (GENERAL SESSION BY POSTER PRESENTATION) (Proceedings of the 30th Annual Meeting)
- 21C-04-2 Correlation between Localization of CYP1A1/2 and Aryl Hydrocarbon Receptor in the Liver Lobule of Rats Treated with 3-methylcholantherene(3MC) or β-Naphthoflavone (BNF).
- Effects of Growth Hormone on Bone in Mini Rats
- Comparison of Bone Changes between Neonatally Monosodium Glutamate-Treated Rats and Mini Rats
- Effects of phenobarbital, a drug-metabolizing enzymes inducer, on hepatic DNA ploidy in hepatectomized rats
- Effect of Glucose Feeding on Regenerating Rat Liver Following Partial Hepatectomy
- "P-36 Hepatic response to continuous cytochrome P450 inhibition in rats sequentially treated with α-hederin.
- Relationship of induction of phase II enzymes to decrease in gap-junctional intercellular communication in rat liver treated with a disinfectant, Etridiazole.
- Correlation between decrease in intercellular communication and phase I enzyme induction in rat liver treated with phenobarbital : an examination of the reversibility during PB-withdrawal.
- DOES GLUCOSE FEEDING POTENTIATE THE TOXICITY OF HEPATOTOXICANTS?
- Induction of Glutathione S-Transferases and Hepatocellular Proliferating Activities in the Rat Liver Treated with tert-Butylated Hydroxyanisole, 1, 2-Bis(2-Pyridyl)Ethylene, and Phenobarbital
- Gene Expression Profiles in the Liver, Placenta and Fetal Liver in Pregnant Rats Treated with T-2 Toxin (TOXICOGENOMICS AND TOXICOPROTEOMICS) (GENERAL SESSION BY POSTER PRESENTATION) (Proceedings of the 30th Annual Meeting)
- Circadian modulation of hepatic transcriptome in transgenic rats expressing human growth hormone
- トログリタゾンによる肝障害の機序解明への薬物動態学的アプローチ - UGTの多型は肝障害の要因となり得るか? -
- Acquired Resistance to Bromobenzene Hepatotoxicity by Repeated Treatment of Rats with Bromobenzene
- EFFECT OF TROGLITAZONE ON THE LIVER OF A GUNN RAT MODEL OF GENETIC ENZYME POLYMORPHISM
- Sex difference and effect of growth hormone on daily fluctuation of hepatic P450 monooxygenase activities in rats.
- Comparison of the Induction Profile of Hepatic Drug-metabolizing Enzymes Between Piperonyl Butoxide and Phenobarbital in Rats
- "B-7 Daily fluctuation of liver metabolic enzymes in F344 rats.
- "A-9 Changes of the liver and kidney in rats treated with tert-butylated hydroxyanisole (BHA).
- LOW GLUTATHIONE S-TRANSFERASE ACTIVITY IN DOG LIVER AND THE MONITORING METHOD
- SEX DIFFERENCE IN INDUCIBILITY OF LIVER DRUG METABOLIZING ENZYMES IN RATS : In particular emphasis on Phase II enzymes
- EFFECTS OF ACETONE(AT) ON HEPATIC MICROSOMAL DRUG-METABOLIZING ENZYMES IN BEAGLE DOGS
- PE-415 Induction of Diacylglycerol O-acyltransferase 1 Gene Induces Tumor Necrosis Factor-α Gene Expression in 3T3-L1 Adipocytes(Diabetes/Obesity/Metabolic syndrome-06, The 71st Annual Scientific Meeting of the Japanese Circulation Society)
- Collaborative work on evaluation of ovarian toxicity : 8) Two- or four-week repeated-dose studies and fertility study of Anastrozole in female rats
- EFFECT OF DIFFERENT DOSES OF β-NAPHTHOFLAVONE(BNF) ON THE LOCALIZATION OF CYTOCHROME P-450 ISOZYMES IN THE LIVER LOBULE OF RATS
- 323 AN IMMUNOHISTOCHENICAL STUDY ON THE LOCALIZATIONS OF CHEMICAL-INDUCIBLE CYTOCHRONE P-450 WITHIN THE RAT LIVER
- Sex and circadian modulatory effects on rat liver as assessed by transcriptome analyses
- Surgical Treatment of Renal Cell Carcinoma with Tumor Thrombi in the Inferior Vena Cava
- A COMPARATIVE STUDY OF HISTAMINE ACTIVITIES ON DIFFERENTIATION OF OSTEOBLASTS AND OSTEOCLASTS
- Establishment and Pathophysiological Characterization of Type 2 Diabetic Mouse Model Produced by Streptozotocin and Nicotinamide(Highlighted paper selected by Editor-in-chief,Pharmacology)
- 老齢B6C3F1マウスの脳小血管における自然発生鉱物質沈着症
- 肝毒性
- Comparative study of histamine H4 receptor expression in human dermal fibroblasts
- Expression of Histamine H4 Receptor in Synovial Cells from Rheumatoid Arthritic Patients(Biopharmacy)
- Histamine H4 Receptor Expression in Human Synovial Cells Obtained from Patients Suffering from Rheumatoid Arthritis(Biopharmacy)
- Cytotoxic Effect of the Her-2/Her-1 Inhibitor PKI-166 on Renal Cancer Cells Expressing the Connexin 32 Gene
- THE EFFECTS OF ASPIRIN AND ITS METABOLITE, SALICYLIC ACID, ON CULTURED RAT EMBRYO
- ACETYLSALICYLIC ACID INDUCED FETALTOXICITY AND DRUG METABOLISM
- Effects of Restricted Feeding on Daily Rhythm of Hepatic P450 Monooxygenase Activities in Male Rats(Drug metabolism, Proceedings of the 32nd Annual Meeting)
- P6-32 Gene analysis on sex difference in the daily rhythm of hepatic P450 monooxygenase activities in rats(DRUG METABOLISM/CARCINOGENICITY)(GENERAL SESSION BY POSTER PRESENTATION)(Proceedings of the 31st Annual Meeting)
- Decrease in protein binding and its effect on toxicokinetics (TK)/toxicodynamics (TD) of diclofenac and propranolol in pregnant rats
- P10-15 The Skeletal Muscle Injury Induced by Sodium Pivalate Is Reversible?
- Comprehensive analysis of hepatic gene and protein expression profiles on phenobarbital- or clofibrate-induced hepatic hypertrophy in dogs
- Toxicogenomic Biomarkers for Liver Toxicity
- Effect of feeding condition on gene expression analysis using DNA chip.(GENERAL SESSION BY POSTER PRESENTATION)(MOLECULAR TOXICITY & TOXICOGENOMICS)
- Gene expression analysis on rat livers treated with L-buthionine (S, R)-sulfoximine : investigation of data compatibility between RG U34A and RAE 230A GeneChips(Toxicogenomics, Toxicoproteomics, Proceedings of the 32nd Annual Meeting)
- Gene expression analysis in rat livers and immune organs treated with isoniazid, phenytoin, hydralazine hydrochloride or chlorpromazine(Proceedings of the 32nd Annual Meeting)
- P6-47 Relationship between hepatic glutathione content and gene expression profile in F344 male rats treated with L-Buthionine(S,R)-sulfoximine(TOXICOGENOMICS)(GENERAL SESSION BY POSTER PRESENTATION)(Proceedings of the 31st Annual Meeting)
- Gene expressions in F344 rat livers treated with acetaminophen or cycloheximide (TOXICOGENOMICS AND TOXICOPROTEOMICS) (GENERAL SESSION BY POSTER PRESENTATION) (Proceedings of the 30th Annual Meeting)
- Effect of aging on gene expression profile in rat livers treated with phenobarbital or clofibrate (TOXICOGENOMICS AND TOXICOPROTEOMICS) (GENERAL SESSION BY POSTER PRESENTATION) (Proceedings of the 30th Annual Meeting)
- Osteosarcomas in the Lungs of an ICR Mouse
- Analysis of nephropathy using DNA chip.(GENERAL SESSION BY POSTER PRESENTATION)(MOLECULAR TOXICITY & TOXICOGENOMICS)
- Gene Expression Analysis on the Rat Liver Treated with Clofibrate or Phenobarbital.(GENERAL SESSION BY POSTER PRESENTATION)(MOLECULAR TOXICITY & TOXICOGENOMICS)
- Immunohistochemical Staining Methods for Connexin32 on Formalin-Fixed Paraffin-Embedded Sections
- Biochemical and immunohistochemical studies on constitutional changes of P450 isozymes during postnatal development in rat liver.
- Pulmonary Histiocytic Sarcoma in Two Aged Dogs of a Beagle Colony
- Relationship between hepatocellular apoptosis and Kupffer cell activation in the livers of rats treated with cycloheximide(Proceedings of the 32nd Annual Meeting)
- Toxicogenoimics, Proteomics and Metabonomics(Toxicity Screening Strategy in Early Stage Drug Development : Current Situation and Perspective, Proceedings of the 32nd Annual Meeting)
- Induction of Cytochrome P450 1A1 in Mice by Repeated Oral Administration of Propranolol
- The Histamine H_2-Receptor Antagonist, Cimetidine, Inhibits the Articular Osteopenia in Rats With Adjuvant-Induced Arthritis by Suppressing the Osteoclast Differentiation Induced by Histamine
- "P-28 Study of reversibility in rat bone changes induced by beta-aminopropionitrile or aminoacetonitrile
- Analysis of Correlation between Prescription Drugs for Climacteric Disorders and CA Repeat Polymorphism of Estrogen Receptor β Gene
- 2-Aryl-1,4-naphthoquinone-1-oxime Methyl Ethers: Their Cytotoxic Activity
- Stereoselective Pharmacokinetics of RS-8359,A Selective and Reversible Inhibitor of A-Type Monoamine Oxidase, in Rats, Mice, Dogs, and Monkeys
- Quantitative determination of diol metabolites of CS-670, a new antiinflammatory agent, by capillary column gas chromatography-mass spectrometry
- 3倍体コイの誘導とその血液学的特徴(速報)〔英文〕
- Effects of monosodium glutamate pretreament on the rat liver changes by clofibrate administration.
- 324 EFFECTS OF PHENOBARBITAL(PB) AND PARTIAL HEPATECTOMY(PH) ON HEPATIC MICROSOMAL DRUG METABOLIZING ENZYMES IN BEAGLE DOGS
- Sensitivity of Steroid Enzyme Immunoassays. Comparison of Alkaline Phosphatase, β-Galactosidase and Horseradish Peroxidase as Labels in a Colorimetric Assay System(Analytical,Chemical)
- COMPARISON OF ENZYMES AS LABELS IN STEROID ENZYME IMMUNOASSAY
- Effect of Nonspecific Binding to Microsomes and Metabolic Elimination of Buprenorphine on the Inhibition of Cytochrome P4502D6(Biochemistry/Molecular Biology)
- DNA DAMAGE MEASURED BY COMET ASSAY AND 8-OH-dG FORMATION RELATED TO BLOOD CHEMICAL ANALYSES IN AGED RATS
- Inhibitory effect of the extracts from Thai medicinal plants on iNOS expression in mouse macrophage RAW 264.7
- Inhibitory effect of oxycoumarins isolated from the Thai medicinal plant Clausena guillauminii on the inflammation mediators, iNOS, TNF-α, and COX-2 expression in mouse macrophage RAW 264.7
- Chromosome Aberrations and Survival in Normal and Dechorionated Embryos of Misgurnus anguillicaudatus (Cobitidae, Pisces) Exposed to Mitomycin C
- Sex Differences in PPARγ Expressions in Rat Adipose Tissues(Biopharmacy)
- Toxicogenomics coupled with proteomics for investigation of drug metabolizing enzymes (WORKSHOP3: CURRENT ISSUES IN PROTEOMICS AND TOXICOGENOMICS) (Proceedings of the 30th Annual Meeting)
- Sex and circadian modulatory effects on rat liver as assessed by transcriptome analyses
- Morphological characteristics of Nigorobuna Carassius auratus grandoculis called Io in Lake Nishino
- INFLUENCE OF MATERNAL DRUG METABOLISM ON THE FETAL TOXICITY INDUCED BY ACETYLSALICYLIC ACID
- Bronchioloalveolar Carcinoma in an Aged Beagle Dog
- Aggravation of Galactosamine Hepatotoxicity by Albumin in Rats
- Development of a Novel Mouse Anaphylaxis Model Produced by Intermittent Intravenous Injections of Ovalbumin without Adjuvant
- Cerivastatin induces type-I fiber-, not type-II fiber-, predominant muscular toxicity in the young male F344 rats
- Thirteen-week Intravenous Toxicity Study of a Novel Humanized Anti-Human Death Receptor 5 Monoclonal Antibody, CS-1008, in Cynomolgus Monkeys
- Toxicogenomic Biomarkers for Liver Toxicity