COMPARATIVE TOXICOLOGICAL ASSESSMENT OF A WATER-SOLUBLE AZOLE ADMINISTERED BOTH ORALLY AND BY INTRAVENOUS CONTINUOUS INFUSION IN CYNOMOLGUS MONKEYS
スポンサーリンク
概要
- 論文の詳細を見る
The water-soluble azole, 4-[1-[1(3-methylaminoacetoxymethyl-pyridin-2-yl)-methyl-car-bamoyloxy]-ethyl]-1 -[(2R,3R)-3-[4-(4-cyano-phenyl)-thiazol-2-yl]-2-(2,5-difluoro-phenyl)-2-hydroxy-butyl]-1H-[1,2,4]triazol-4-ium chloride hydrochloride (hereinafter referred to as WSA), is a new water-soluble triazole anti-fungal compound. WSA is rapidly converted into its active metabolite after administration by either the intravenous or oral route. The clinical effects of WSA are expected to be consistent whether it is administered by injection (intravenous) or orally. To evaluate and compare the toxicities of WSA via oral and intravenous administration, repeated toxicity studies of WSA were conducted in cynomolgus monkeys (oral dosage levels: 0, 10, 30 and 90 mg/kg/day over a 4-week period; intravenous infusion dosage levels: 0, 10, 30 and 60 mg/kg/day over a 2-week period). In addition, a 2-week oral toxicity study of the active metabolite of WSA was conducted with similar dosages (0, 10, 30 and 90 mg/kg/day). From the results obtained from the evaluation, hepatotoxicity (liver) and endocrinological toxicity (adrenals) were the major toxicities, a finding which is comparable to other previously tested azole compounds. In the 4-week oral toxicity study, the lethal dose of WSA was determined to be 90 mg/kg. However, no animal mortality was observed during the 2-week intravenous continuous infusion study. The toxicokinetics (TK) profile of WSA at 10 and 30 mg/kg dosages illustrated a rapid, dose-dependent conversion of WSA to its active metabolite, and the plasma levels of C_<max> and AUG were well correlated to their toxicities. However, at high dosages (60 and 90 mg/kg), WSA demonstrated high exposure beyond the dose-proportional manner. Overall, the results obtained indicate that maintaining an effective concentration and a non-toxic dosage level would be manageable by utilizing an initial intravenous continuous infusion followed by oral administration.
- 日本トキシコロジー学会の論文
- 2002-05-17
著者
-
Kobayashi Kazuko
中外製薬
-
Kobayashi Kazuko
Department of Toxicology and Pathology, Nippon Roche K.K.Research Center
-
Horii Ikuo
Department of Toxicology and Pathology, Nippon Roche K.K.Research Center
-
Horii Ikuo
Department Of Preclinical Science Nippon Roche K. K. Research Center
-
KOBAYASHI kazuko
CHUGAI PHARMACEUTICAL CO., LTD.
-
Kobayashi Kazuko
Department Of Radiology St Marianna University School Of Medicine
-
Kobayashi Kazuko
Research Compliance & Quality Assurance Coordination Department Research Division Chugai Pharmac
-
Kobayashi Kazuko
Department Of Cell Chemistry Okayama University Graduate School Of Medicine And Dentistry
-
Horii Ikuo
Department Of Biochemical Toxicology School Of Pharmacy Showa University
関連論文
- Toxicological assessment of a novel anti-tumor agent Capecitabine (Ro 09-1978, 5'-DFCR derivative : Species differences and improvement of intestinal toxicity
- Toxicological assessment of a novel anti-tumor agent Capecitabine (Ro 09-1978, 5'-DFCR derivative) : Toxicokinetics in monkeys, rats and mice
- ASSESSMENT OF QUANTITATIVE DUAL-PARAMETER FLOW CYTOMETRIC ANALYSIS FOR THE EVALUATION OF TESTICULAR TOXICITY USING CYCLOPHOSPHAMIDE -AND ETHINYLESTRADIOL- TREATED RATS
- FLOW CYTOMETRIC ANALYSIS FOR SPERM VIABILITY AND COUNTS IN RATS TREATED WITH TRIMETHYLPHOSPHATE OR PYRIDOXINE
- Flow cytometric analysis of sperm viability and number in the rats treated with Trimethylphosphate and Ornidazole.
- CHALLENGE TO IN VITRO ANTIGENICITY STUDY IN HUMAN LYMPHOCYTES : ESTABLISHMENT OF TEST SYSTEM USING HETEROGENEOUS PROTEINS AS ANTIGENS
- Prediction of drug-induced QT interval prolongation in telemetered common marmosets
- Evaluation of drug-induced QT prolongation in conscious marmosets(Circulatory system, Proceedings of the 32nd Annual Meeting)
- Antigenic structures recognized by anti-β2-glycoprotein I auto-antibodies
- MALE FERTILITY IN RATS TREATED WITH ETRETINATE FOR 4 WEEKS (<SPECIAL ISSUE>TESTICULAR TOXICITY)
- EFFECT OF ETRETINATE (AROMATIC RETINOID) TREATMENT DURING GESTATION AND LACTATION PERIODS ON VIABILITY AND SOMATIC GROWTH IN F1 RATS
- EFFECT OF 1,25-DIHYDROXYVITAMIN D_3 ON THE FEMALE REPRODUCTIVE SYSTEM IN RATS
- "A-12 Investigation of SCID mice transferred with human lymphocytes (hu-PBL-SCID mice) for the evaluation of toxicity on human immune system. : Human immunoglobulin production in hu-PBL-SCID mice
- P-80 Comparative 4 AND 2 Weeka Oral Repeated Dosing Studies On Male Reproductive Organs in Rats Treated With 5-Fluorouracil.(Proceedings of the 27th Annual Meeting)
- COLLABORATIVE WORK TO EVALUATE TOXICITY ON MALE REPRODUCTIVE ORGANS BY REPEATED DOSE STUDIES IN RATS : 18)COMPARATIVE 4 AND 2 WEEKS ORAL REPEATED DOSING STUDIES ON MALE REPRODUCTIVE ORGANS IN RATS TREATED WITH 5-FLUOROURACIL
- COMPARATIVE TOXICOLOGICAL ASSESSMENT OF A WATER-SOLUBLE AZOLE ADMINISTERED BOTH ORALLY AND BY INTRAVENOUS CONTINUOUS INFUSION IN CYNOMOLGUS MONKEYS
- TOXICOKINETICS:ITS SIGNIFICANCE AND PRACTICAL PROBLEMS
- Radiologist supply and workload : international comparison : Working Group of Japanese College of Radiology
- EFFECTS OF DOXIFLURIDINE(DFUR)ON MOUSE THYMOCYTE DIFFERENTIATION
- Investigation of culture conditions of rat cardiomyocytes for in vitro evaluation of cardiotoxicity 2 : Analysis of Collagen gel + Matrigel culture(Circulatory system, Proceedings of the 32nd Annual Meeting)
- EFFECTS ON FETAL THYMOCYTE POPULATIONS AND POSTNATAL T-CELL-DEPENDENT IMMUNE FUNCTIONS AFTER MATERNAL EXPOSURE TO 5-FLUOROURACIL DURING PREGNANCY IN MICE
- Report 3 : FUTURE PROSPECTS FOR TOXICOKINETICS : ITS ABILITY TO PREDICT DRUG ADVERSE EVENTS IN HUMANS (TOXICOKINETICS)
- COMPARATIVE IMMUNOTOXICITY ASSESSMENT OF N^4-TRIMETHOXYBENZOYL-5'-DEOXY-5-FLUOROCYTIDINE (RO 09-1390) AND 5'-DEOXY-5-FLUOROURIDINE (5'-DFUR) IN BDF1 MICE
- 2B-22 Homologous passive cutaneous anaphylaxis test in mice
- Inhibitory effect of endothelin receptor antagonist on growth of 3T3-E1 osteoblastic cells in vitro.
- AROMATIC RETINOID RO 40-8757 REDUCES IMMUNOTOXICITIES OF CYCLOPHOSPHAMIDE AS REVEALED BY IMMUNOHISTOCHEMICAL STAINING OF LYMPHOID TISSUES AND GENERAL PATHOLOGIC EXAMINATIONS
- Investigation of in vitro antigenicity study by using dendritic cells induced from mouse bone marrow cells. Expression of cell surface markers by exposure to antigens.(GENERAL SESSION BY ORAL PRESENTATION)(IMMUNE AND ALLERGIC SYSTEM)
- ENDOCRINOLOGICAL ASSESSMENT OF TOXIC EFFECTS ON THE MALE REPRODUCTIVE SYSTEM IN RATS TREATED WITH 5-FLUOROURACIL FOR 2 OR 4 WEEKS
- O12-14 Significant endocrinological parameters for the assessment of male reproductive toxicity induced by 1, 3-Dinitrobenzene or Taxol
- 6-Mercaptopurine-induced histopathological changes and xanthine oxidase expression in rat placenta
- Effects of the Fluoroquinolone Antibacterial Drug Ciprofloxacin on Ventricular Repolarization in the Halothane-Anesthetized Guinea Pig
- Importance of the Nucleotide Loop Moiety Corrdinated to the Cobalt Atom of Adenosylcobalamin for Coenzymic Function in the Diol Dehydrase Reaction.
- Oxidative cleavage of tin-tin bonds in hexaalkyldistannane with several 1,4-benzoquinones. Detection of the semiquinone radicals and 4-(trialkylstannoxy)phenoxyl radicals by ESR spectroscopy.
- The Conventional Antihistamine Drug Cyproheptadine Lacks QT-interval–Prolonging Action in Halothane-Anesthetized Guinea Pigs: Comparison With Hydroxyzine
- Microarray analysis of 6-mercaptopurine-induced-toxicity-related genes and microRNAs in the rat placenta