ダカルバジン 化学特性,用途語,生産方法
外観
白色〜うすい黄色, 結晶性粉末〜粉末
溶解性
水に溶けにくく、エタノール及びアセトンにほとんど溶けない。
用途
アルキル化剤です。代謝で生
じたジアゾメタンを介したアルキル化作用に
より DNA の障害を引き起こします。
用途
がん研究用試薬。
効能
抗悪性腫瘍薬, アルキル化剤
商品名
ダカルバジン (協和発酵キリン)
説明
Dacarbazine is nevertheless considered the first representative of the series of triazene
derivatives. It has been shown that it is an alkylating agent, and thus this drug inhibits RNA
and protein synthesis to a greater degree than DNA. Dacarbazine is used intravenously for
Hodgkin’s disease, soft-tissue sarcoma, and metastatic melanoma. A synonym of this drug
is diticene.
化学的特性
Dacarbazine is a white to ivory-colored
crystalline solid.
使用
Dacarbazine is used as an antineoplastic for treatment of malignant melanoma and sarcomas.
定義
ChEBI: A monocarboxylic acid amide that is 1H-imidazole-4-carboxamide which is substituted at position 5 by a 3,3-dimethyltriaz-1-en-1-yl group. It is used for the treatment of metastatic malignant melanoma, and in combination with other drugs
or the treatment of Hodgkin's disease and soft-tissue sarcoma.
適応症
Dacarbazine (DTIC-Dome) is activated by photodecomposition
and by enzymatic N-demethylation.
Eventual formation of a methyl carbonium ion results
in methylation of DNA and RNA and inhibition of nucleic
acid and protein synthesis. As with other alkylating
agents, cells in all phases of the cell cycle are susceptible
to dacarbazine.
The plasma half-life of dacarbazine is biphasic, with
a distribution phase of 19 minutes and an elimination
phase of 5 hours. The drug is not appreciably protein
bound, and it does not enter the central nervous system
(CNS). Urinary excretion of unchanged drug is by renal
tubular secretion. Dacarbazine metabolism and decomposition
is complex.
Dacarbazine is the most active agent used in metastatic
melanoma, producing a 20% remission rate. It is also
combined with doxorubicin and other agents in the treatment
of various sarcomas and Hodgkin’s disease.
Dacarbazine may cause severe nausea and vomiting.
Leukopenia and thrombocytopenia occur 2 weeks after
treatment, with recovery by 3 to 4 weeks. Less common
is a flulike syndrome of fever, myalgias, and malaise.
Alopecia and transient abnormalities in renal and hepatic
function also have been reported.
一般的な説明
Dacarbazine is available in 100- and 200-mg vials for IVadministration in the treatment of Hodgkin’s disease, malignantmelanoma, carcinoid cancer, neuroblastoma, andsoft tissue sarcoma. Resistance to dacarbazine has been primarilyattributed to enhanced activity of AGAT. The volumeof distribution exceeds the amount of water in thebody suggesting the compound distributes into body tissuespossibly the liver. The agent is not highly protein bound(20%) and is metabolized in the liver by CYP to give MTICand 4-amino-5-imidazole-carboxamide (AIC).Thedemethylation reaction is mediated by isozymes CYP1A1/2and CYP2E1. Elimination occurs via the urine with 40% to50% occurring as unchanged drug. Dose-limiting myelosuppressionpresents as both leucopenia and thrombocytopenia.Other adverse effects include nausea, vomiting,flulike symptoms, photosensitivity, and pain at the injectionsite.
空気と水の反応
Insoluble in water.
反応プロフィール
Dacarbazine decomposes explosively at its melting point (250°C). Decomposes in the presence of light. Sensitive to oxidation.
火災危険
Flash point data for Dacarbazine are not available. Dacarbazine is probably combustible.
臨床応用
This DNA methylating agent is administered IV as a single agent in the treatment of malignant melanoma and in combination with other agents in the treatment of metastatic melanoma.
副作用
Approximately 40% of the drug is excreted unchanged, but both the 5-aminoimidazole-4-carboxamide (AIC, formed through the action of CYP1A enzymes) and the carboxylic acid (AIC hydrolysis product) are major urinary metabolites. Leukopenia and thrombocytopenia are the most common side effects and may be fatal. Patients also are at risk for hepatotoxicity, including hepatocellular necrosis.
安全性プロファイル
Confirmed carcinogen
with experimental carcinogenic and
tumorigenic data. Poison by intraperitoneal
and parenteral routes. Moderately toxic by
ingestion and intravenous routes.
Experimental teratogenic effects. Human
systemic effects by intravenous route:
nausea or vomiting, leukopenia (reduced
white blood cell count), and changes in
dehydrogenase enzymatic activity. Mutation
data reported. When heated to
decomposition it emits toxic fumes of NOx.
職業ばく露
Dacarbazine is used in cancer chemo-
therapy. Dacarbazine is used as an antineoplastic agent in
the treatment of certain skin cancers, and is occasionally
used in the therapy of other neoplastic diseases which have
become resistant to alternative treatment.br Health professionals who handle this drug (for example,
pharmacists, nurses, and physicians) may possibly be
exposed during drug preparation, administration, or cleanup;
however, the risks can be avoided through use of appropriate
containment equipment and work practices
.People
receiving dacarbazine in treatment are also exposed.
環境運命予測
The exact mechanism of action of dacarbazine is unknown;
however, several proposed mechanisms have been made
including inhibition of DNA synthesis by acting as a purine
analog, alkylating agent, and interference with sulfhydryl
groups. It is most commonly classified as an alkylating agent in
the triazene group. While the active compound of dacarbazine,
DTIC, is structurally similar to purines, its primary mechanism
of action precludes the agent from being classified as an antimetabolite.
Dacarbazine is a synthetic compound that is
metabolically activated to the active alkylating metabolite
methyl-triazeno-imidazole-carboxamide (MTIC) via the cytochrome
P450 system, primarily CYP1A1, CYP1A2, and CYP
2E1. MTIC is rapidly tautomerized into an inactive derivative,
5-aminoimidazole-4-carboxamide (AIC), which is renally
excreted. The entire process of activating DTIC occurs within
15 min of intravenous infusion. DTIC exerts its actions
throughout all phases of the cellular cycle. The antitumor
effects of this compound are related to the induction of methyl
adducts to DNA. The 70% of alkylation occurs at the N
7
position of guanine. The cytotoxic and mutagenic effects of
MTIC are manifested through alkylation of DNA at the O
6
guanine position, accounting for 6–8% of methylated bases
formed. This is primarily a result of generation of incorrect base
pairing, leading to DNA double strand breaks and apoptosis.
輸送方法
UN3249 Medicine, solid, toxic, n.o.s., Hazard
Class: 6.1; Labels: 6.1-Poisonous materials.
不和合性
ncompatible with oxidizers (chlorates,
nitrates, peroxides, permanganates, perchlorates, chlorine,
bromine, fluorine, etc.); contact may cause fires or explo-
sions. Keep away from alkaline materials, strong bases,
strong acids, oxoacids, and epoxides. Explosive decom-
position reported @ 250℃
255℃
廃棄物の処理
It is inappropriate and possi-
bly dangerous to the environment to dispose of expired or
waste drugs and pharmaceuticals by flushing them down
the toilet or discarding them to the trash. Household quanti-
ties of expired or waste pharmaceuticals may be mixed
with wet cat litter or coffee grounds, double-bagged in
plastic, discard in trash. Larger quantities shall carefully
take into consideration applicable DEA, EPA, and FDA
regulations. If possible return the pharmaceutical to the
manufacturer for proper disposal being careful to properly
label and securely package the material. Alternatively, the
waste pharmaceutical shall be labeled, securely packaged
and transported by a state licensed medical waste contractor
to dispose by burial in a licensed hazardous or toxic waste
landfill or incinerator.
ダカルバジン 上流と下流の製品情報
原材料
準備製品