フルオロウラシル
|
|
| IUPAC命名法による物質名 |
| 5-Fluoropyrimidine-2,4(1H,3H)-dione |
| 臨床データ |
| 胎児危険度分類 |
- |
| 法的規制 |
劇薬
指定医薬品
処方せん医薬品 |
| 投与方法 |
静注、点滴静注、経口投与 |
| 薬物動態的データ |
| 生物学的利用能 |
28～100% |
| 血漿タンパク結合 |
7.5～10.3% |
| 代謝 |
異化代謝:肝臓（DPD酵素）
同化代謝:腫瘍、脾臓、胃など（thymidine phospholylase, uridine phospholylase, orotate phosphoribosyl transferase） |
| 半減期 |
10-20 minutes |
| 排泄 |
尿中、胆汁中 |
| 識別 |
| CAS登録番号 |
51-21-8 |
| ATCコード |
L01BC02 |
| PubChem |
CID 3385 |
| KEGG |
D00584 |
| 化学的データ |
| 化学式 |
C4H3FN2O2 |
| 分子量 |
130.077 |
フルオロウラシル（fluorouracil）は、フッ化ピリミジン系の代謝拮抗剤で、抗悪性腫瘍薬（抗がん剤）。ウラシルの5位水素原子がフッ素原子に置き換わった構造をしている。
1956年にDushinskyらによって合成され、その後Heidelbergerらを中心として基礎および臨床にわたる広範な研究で抗悪性腫瘍剤としての評価が確立された。
代表商品は「5-FU XX（剤形）協和」（協和発酵キリン）。古くから有るため、ジェネリック医薬品も多数流通している。 また、1990年代よりフルオロウラシルをプロドラッグ化などの改良を施し、より強い効果が期待される薬剤（内用薬）が開発され、上市されているもある。（テガフール・ウラシル・TS-1/ゼローダなど）
目次
- 1 承認された効能・効果
- 1.1 注
- 1.2 錠・ドライシロップ
- 1.3 坐剤
- 1.4 軟膏
- 2 併用療法
- 3 作用機序
- 4 プロドラッグ
- 5 重大な副作用
- 6 併用禁忌
- 7 参考資料
- 8 関連事項
- 9 外部リンク
承認された効能・効果
代表的な「5-FU XX 協和」の場合、注（注射薬）・錠・ドライシロップ（内用薬）・坐剤/軟膏（外用薬）の剤形があり、用途に応じて複数の主成分量毎に商品化がされている。なお、「5-FUドライシロップ5%協和」については、2009年3月末で販売終了する（ジェネリック医薬品が実質的な代用製品となる）。
注
- 下記疾患の自覚的並びに他覚的症状の緩解
- 胃癌、肝癌、結腸・直腸癌、乳癌、膵臓癌、子宮頸癌、子宮体癌、卵巣癌
- 下記の疾患については、他の抗癌剤または放射線療法と併用。
- 他の抗悪性腫瘍剤との併用療法
錠・ドライシロップ
坐剤
軟膏
- 皮膚悪性腫瘍（有棘細胞癌、基底細胞癌、皮膚附属器癌、皮膚転移癌・悪性リンパ腫の皮膚転移、ボーエン病、パジェット病、放射線角化腫、老人性角化腫、紅色肥厚症、皮膚細網症）
適用外使用として、ブレオマイシン軟膏と並んで癌以外の疾病にも医師の裁量で用いられる場合がある（皮膚科→イボ・ウオノメ、婦人科・性病科→尖圭コンジローマが代表例）。外国製品の個人輸入が専ら取り扱われているが、強力な薬剤（劇薬指定）でかつ抗がん剤であるため素人が扱うべきものではない。
併用療法
効果を最大限に発揮させる用法であるが、強い副作用等が予測されるため、治療に熟知した医師の判断の下で行われることが望ましいとされている。
- 5-FU/ロイコボリン（LV）療法
- 5-FU/レボホリナート療法
作用機序
本剤およびその代謝物が核酸の合成を阻害（代謝拮抗）し、抗腫瘍効果を表す。詳しくは以下述べる。
DNA合成阻害
5-FUは体内でリン酸化され、活性本体である「5-フルオロデオキシウリジン-5'-一リン酸（fluorodeoxyuridine-5'-monophosphate :FdUMP）」となり、補酵素で還元型葉酸として存在する「5,10-メチレンテトラヒドロ葉酸]](N 5,10-methylenetetrahydrofolate)」の存在下に、チミジル酸合成酵素(TS)と三元共有結合複合体(ternary complex)を形成することで、TS活性を阻害する。TS活性が阻害されるとチミンの合成が阻害され、DNAが作れなくなる。
また、5-FUは体内で「5-フルオロデオキシウリジン-5'-一リン酸（fluorodeoxyuridine-5'-monophosphate :FdUMP）」となり、これがDNAに組み込まれることでも、DNA合成が阻害される。
RNA合成阻害
5-FUは体内で「5-フルオロウリジン三リン酸(FUTP)に代謝され、UTPの代わりにRNAに組み込まれることで、F-RNAを生成し、RNAプロセシング及び、mRNA翻訳を妨げる。
プロドラッグ
5-FUを親化合物として、作用の持続性向上やターゲッティング（選択的移行性向上）を目的としていくつものプロドラッグが開発されている。作用持続化を目的としたものに、テガフール、カルモフールがあり、ターゲッテングを目的としたものに、ドキシフルリジン、カペシタビンがある。
また、抗真菌薬として、真菌細胞内で代謝され、効果を発揮するフルシトシン(5-FC)がある。これはヒトの体内では5-FUになることはない。
重大な副作用
脱水症状、重篤な腸炎、骨髄機能抑制、ショック、アナフィラキシー様症状、白質脳症、うっ血性心不全、心筋梗塞、安静狭心症、急性腎不全、間質性肺炎、肝機能障害、黄疸、消化管潰瘍、重症な口内炎、急性膵炎、意識障害を伴う高アンモニア血症、肝・胆道障害（胆嚢炎、胆管壊死、肝実質障害等）、手足症候群、嗅覚障害
併用禁忌
ソリブジン
ソリブジン（商品名:ユースビル、日本商事製造販売・エーザイ共同販売）は、癌による免疫力低下で発生するリスクが高い帯状疱疹の治療薬として、1993年に上市された。代謝物がフルオロウラシルの代謝を阻害して副作用を強く出現させる。そのため、ユースビルが発売されて間も無く、5-FUの類を投与されていた癌患者を中心に15人の死者を出す一大薬害を引き起こした。
発生機序としてソリブジンは体内でブロモビニルウラシルに代謝される。このブロモビニルウラシルはフルオロウラシルの代謝酵素と結合して不可逆的に阻害することによりフルオロウラシルの蓄積が生じる。このことにより骨髄抑制などの中毒症状を引き起こす。
なお、「ソリブジン事件/薬害」と称される5-FUとの相互作用問題から、1993年にユースビルの自主回収後に承認が取り下げられ、製造打ち切りから相当期間が経過したため、1999年12月までに5-FUなど相互作用が関係する医薬品添付文書から併用禁忌を含めソリブジン（ユースビル）に関する記述は削除された。
TS-1
TS-1は、テガフールという5-FUのプロドラッグと拮抗剤の複合薬で、5-FU製剤を併用するとフルオロウラシルの代謝を阻害することとなり、血中濃度を上げる。
参考資料
- 『5-FU注250協和』医薬品インタビューフォーム・2006年1月作成（協和発酵工業）
関連事項
- 協和発酵キリン
- 化学療法 (悪性腫瘍)
- 抗がん剤
- 日本商事 - ソリブジン薬害事件を引き起こした
外部リンク
- ソリブジン薬害発生の分子毒性学的メカニズムとジヒドロピリミジン・デヒドロゲナーゼの遺伝的欠損
"F5U" redirects here. For the Flying Flapjack, see Vought XF5U.
Fluorouracil
|
|
| Systematic (IUPAC) name |
| 5-fluoro-1H,3H-pyrimidine-2,4-dione |
| Clinical data |
| Trade names |
Adrucil, Carac, Efudex |
| AHFS/Drugs.com |
monograph |
| MedlinePlus |
a682708 |
| Licence data |
US FDA:link |
| Pregnancy cat. |
D (AU)
D (IV), X (topical) (US) |
| Legal status |
Prescription Only (S4) (AU) ℞-only (CA) POM (UK) ℞-only (US) |
| Routes |
IV (infusion or bolus) and topical |
| Pharmacokinetic data |
| Bioavailability |
28 to 100% |
| Protein binding |
8 to 12% |
| Metabolism |
Intracellular and hepatic (CYP-mediated) |
| Half-life |
16 minutes |
| Excretion |
Renal |
| Identifiers |
| CAS number |
51-21-8 Y |
| ATC code |
L01BC02 |
| PubChem |
CID 3385 |
| DrugBank |
DB00544 |
| ChemSpider |
3268 Y |
| UNII |
U3P01618RT Y |
| KEGG |
D00584 Y |
| ChEBI |
CHEBI:46345 Y |
| ChEMBL |
CHEMBL185 Y |
| Chemical data |
| Formula |
C4H3FN2O2 |
| Mol. mass |
130.077 g/mol |
SMILES
- c1c(c(=O)[nH]c(=O)[nH]1)F
|
InChI
-
InChI=1S/C4H3FN2O2/c5-2-1-6-4(9)7-3(2)8/h1H,(H2,6,7,8,9) Y
Key:GHASVSINZRGABV-UHFFFAOYSA-N Y
|
| Physical data |
| Melt. point |
282 - 283 °C (-195 °F) |
| Y (what is this?) (verify) |
Fluorouracil // or 5-FU (trademarked as Adrucil (IV), Carac (topical), Efudex (topical)) is a drug that is a pyrimidine analog which is used in the treatment of cancer. It is a suicide inhibitor and works through irreversible inhibition of thymidylate synthase. It belongs to the family of drugs called the antimetabolites.[1]
It is on the World Health Organization's List of Essential Medicines, a list of the most important medication needed in a basic health system.[2]
Contents
- 1 Medical uses
- 2 Adverse effects
- 2.1 Contraindications
- 2.2 Interactions
- 2.3 Dosing concerns
- 3 Mechanism of action
- 4 Synthesis
- 5 History
- 6 Interactive pathway map
- 7 References
- 8 External links
Medical uses
Fluorouracil has been given systemically for anal, breast, colorectal, oesophageal, stomach, pancreatic and skin cancers (especially head and neck cancers).[3] It has also been given topically for actinic keratoses and Bowen's disease.[3]
Adverse effects
Adverse effects by frequency:[3][4][5][6][7][8]
During systemic use:
Common (>1% frequency):
- Nausea
- Vomiting
- Diarrhoea (see below for details)
- Mucositis
- Headache
- Myelosuppression (see below for details)
- Alopecia (hair loss)
- Photosensitivity
- Hand-foot syndrome
- Maculopapular eruption
- Itch
- Cardiotoxicity (see below for details)
Uncommon (0.1-1% frequency):
- Oesophagitis
- GI ulceration and bleeding
- Proctitis
- Nail disorders
- Vein pigmentation
- Confusion
- Cerebellar syndrome
- Encephalopathy
- Visual changes
- Photophobia
- Lacrimation (the expulsion of tears without any emotional or physiologic reason)
Rare (<0.1% frequency):
- Anaphylaxis
- Allergic reactions
- Fever without signs of infection
Diarrhoea is severe and may be dose-limiting and is exacerbated by co-treatment with calcium folinate.[3] Neutropenia tends to peak about 9-14 days after beginning treatment.[3] Thrombocytopenia tends to peak about 7-17 days after the beginning of treatment and tends to recover about 10 days after its peak.[3] Cardiotoxicity is a fairly common side effect, but usually this cardiotoxicity is just angina or symptoms associated with coronary artery spasm, but in about 0.55% of those receiving the drug will develop life-threatening cardiotoxicity.[9] Life-threatening cardiotoxicity includes: arrhythmias, ventricular tachycardia and cardiac arrest, secondary to transmural ischaemia.[9]
During topical use:[3][7]
Common (>1% frequency):
- Local pain
- Itchiness
- Burning
- Stinging
- Crusting
- Weeping
- Dermatitis
- Photosensitivity
Uncommon (0.1-1% frequency):
- hyper- or hypopigmentation
- Scarring
Contraindications
It is contraindicated in patients that are severely debilitated or in patients with myelosuppression due to either radiotherapy or chemotherapy.[6] It is likewise contraindicated in pregnant or breastfeeding women.[6] It should also be avoided in patients that do not have malignant illnesses.[6]
Interactions
Its use should be avoided in patients receiving drugs known to modulate dihydropyrimidine dehydrogenase (such as the antiviral drug, sorivudine).[6] It may also increase the INR and prothrombin times in patients on warfarin.[6]
Dosing concerns
There is very little difference between the minimum effective dose and maximum tolerated dose of 5-FU, and the drug exhibits marked individual pharmacokinetic variability.[10][11][12] Therefore, an identical dose of 5-FU may result in a therapeutic response with acceptable toxicity in some patients and unacceptable and possibly life threatening toxicity in others.[10] Both overdosing and underdosing are of concern with 5-FU, although several studies have shown that the majority of colorectal cancer patients treated with 5-FU are underdosed based on today's dosing standard, body surface area (BSA).[13][14][15][16] The limitations of BSA-based dosing prevent oncologists from being able to accurately titer the dosage of 5-FU for the majority of individual patients, which results in sub-optimal treatment efficacy or excessive toxicity.[13][14]
Numerous studies have found significant relationships between concentrations of 5-FU in blood plasma and both desirable or undesirable effects on patients.[17][18] Studies have also shown that dosing based on the concentration of 5-FU in plasma can greatly increase desirable outcomes while minimizing negative side effects of 5-FU therapy.[13][19] One such test that has been shown to successfully monitor 5-FU plasma levels and which "may contribute to improved efficacy and safety of commonly used 5-FU-based chemotherapies" is the My5-FU test.[15][20][21]
Mechanism of action
The chemotherapy agent 5-FU, which has been used against cancer for about 40 years, acts in several ways, but principally as a thymidylate synthase (TS) inhibitor. Interrupting the action of this enzyme blocks synthesis of the pyrimidine thymidine, which is a nucleoside required for DNA replication. Thymidylate synthase methylates deoxyuridine monophosphate (dUMP) to form thymidine monophosphate (dTMP). Administration of 5-FU causes a scarcity in dTMP, so rapidly dividing cancerous cells undergo cell death via thymineless death.[22] Calcium folinate provides an exogenous source of reduced folinates and hence stabilise the 5-FU-TS complex hence enhancing 5-FU's cytotoxicity.[23]
Synthesis
5-FU was designed, synthesized and patented by Charles Heidelberger in 1957.[24][25]
Since uracil is a normal component of RNA, the rationale behind the development of the drug was that cancer cells, with their increased genetic instability, might be more sensitive to 'decoy' molecules that mimic the natural compound than normal cells. The scientific goal in this case was to synthesize a drug which demonstrated specific uracil antagonism. The drug proved to have anti-tumor capabilities.
When elemental fluorine is reacted with uracil, 5-fluorouracil is produced. 5-Fluorouracil masquerades as uracil during the nucleic acid replication process. Because 5-fluorouracil is similar in shape to but does not perform the same chemistry as uracil, the drug inhibits RNA replication enzymes, thereby eliminating RNA synthesis and stopping the growth of cancerous cells.
History
In 1954 Abraham Cantarow and Karl Paschkis found liver tumors absorbed radioactive uracil more readily than normal liver cells. Charles Heidelberger, who had earlier found that fluorine in fluoroacetic acid inhibited a vital enzyme, asked Robert Duschinsky and Robert Schnitzer at Hoffman-La Roche to synthesize fluorouracil.[26] Some credit Heidelberger and Duschinsky with the discovery that 5-fluorouracil markedly inhibited tumors in mice.[27] The original 1957 report in Nature has Heidelberger as lead author, along with N.K.Chaudhuri, Peter Danneberg, Dorothy Mooren, Louis Griesbach, Robert Duschinsky, R.J. Schnitzer, E. Pleven, and J. Scheiner.[28]
Interactive pathway map
Click on genes, proteins and metabolites below to link to respective articles. [§ 1]
Fluorouracil (5-FU) Activity edit
- ^ The interactive pathway map can be edited at WikiPathways: "FluoropyrimidineActivity_WP1601".
References
- ^ Brayfield, A, ed. (13 December 2013). "Fluorouracil". Martindale: The Complete Drug Reference. Pharmaceutical Press. Retrieved 16 April 2014.
- ^ "WHO Model List of EssentialMedicines". World Health Organization. October 2013. Retrieved 22 April 2014.
- ^ a b c d e f g Rossi, S, ed. (2013). Australian Medicines Handbook (2013 ed.). Adelaide: The Australian Medicines Handbook Unit Trust. ISBN 978-0-9805790-9-3. edit
- ^ "DBL™ FLUOROURACIL INJECTION BP" (PDF). TGA eBusiness Services. Hospira Australia Pty Ltd. 21 June 2012. Retrieved 24 January 2014.
- ^ "ADRUCIL (fluorouracil) injection [Teva Parenteral Medicines, Inc.]". DailyMed. Teva Parenteral Medicines, Inc. August 2012. Retrieved 24 January 2014.
- ^ a b c d e f "Fluorouracil 50 mg/ml Injection - Summary of Product Characteristics". electronic Medicines Compendium. Hospira UK Ltd. 24 August 2011. Retrieved 24 January 2014.
- ^ a b "Efudex, Carac (fluorouracil topical) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Retrieved 24 January 2014.
- ^ "Adrucil (fluorouracil) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Retrieved 24 January 2014.
- ^ Cite error: The named reference
MD was invoked but never defined (see the help page).
- ^ a b Gamelin, E.; Boisdron-Celle, M (1999). Dose monitoring of 5-fluorouracil in patients with colorectal or head and neck cancer—status of the art 30 (1). Critical Reviews in Oncology/Hematology. pp. 71–79.
- ^ Felici A.; J. Verweij; A. Sparreboom (2002). Dosing strategies for anticancer drugs: the good, the bad and body-surface area 38 (13). Eur J Cancer. pp. 1677–84.
- ^ Baker SD; Verweij J; Rowinsky EK; Donehower RC; Schellens JH; Grochow LB; Sparreboom A (2002). Role of body surface area in dosing of investigational anticancer agents in adults, 1991-2001 94 (24). J Natl Cancer Inst. pp. 1883–8.
- ^ a b c Capitain O; Asevoaia A; Boisdron-Celle M; Poirier AL; Morel A; Gamelin E (2012). Individual Fluorouracil Dose Adjustment in FOLFOX Based on Pharmacokinetic Follow-Up Compared With Conventional Body-Area-Surface Dosing: A Phase II, Proof-of-Concept Study 11 (4). Clin Colorectal Cancer. pp. 263–267.
- ^ a b Saam, J; Critchfield GC; Hamilton SA; Roa BB; Wenstrup RJ; Kaldate RR (2011). Body surface area-based dosing of 5-fluoruracil results in extensive interindividual variability in 5-fluorouracil exposure in colorectal cancer patients on FOLFOX regimens 10 (3). Clin Colorectal Cancer. pp. 203–6.
- ^ a b Beumer JH; Boisdron-Celle M; Clarke W; Courtney JB; Egorin MJ; Gamelin E; Harney RL; Hammett-Stabler C; Lepp S; Li Y; Lundell GD; McMillin G; Milano G; Salamone SJ (2009). Multicenter evaluation of a novel nanoparticle immunoassay for 5-fluorouracil on the Olympus AU400 analyzer 31 (6). Ther Drug Monit. pp. 688–94.
- ^ Goldberg RM; Rothenberg ML; Van Cutsem E; Benson AB 3rd; Blanke CD; Diasio RB; Grothey A; Lenz HJ; Meropol NJ; Ramanathan RK; Becerra CH; Wickham R; Armstrong D; Viele C (2007). The Continuum of Care: A Paradigm for the Management of Metastatic Colorectal Cancer 12. The Oncologist. pp. 38–50.
- ^ Ploylearmsaeng, S.-a.; U. Fuhr; A. Jetter (2006). How may Anticancer Chemotherapy with Fluorouracil be Individualised? 45 (6). Clin Pharmacokinet. pp. 567–92.
- ^ van Kuilenburg, A.B.; J.G. Maring (2013). Evaluation of 5-fluorouracil pharmacokinetic models and therapeutic drug monitoring in cancer patients 14 (7). Pharmacogenomics. pp. 799–811.
- ^ Gamelin EC; Delva R; Jacob J; Merrouche Y; Raoul JL; Pezet D; Dorval E; Piot G; Morel A; Boisdron-Celle M (2008). Individual fluorouracil dose adjustment based on pharmacokinetic follow-up compared with conventional dosage: Results of a multicenter randomized trial of patients with metastatic colorectal cancer 26 (13). J Clin Oncol. pp. 2099–2105.
- ^ "Customizing Chemotherapy for Better Cancer Care". My Care Diagnostics.
- ^ "A Brief History of BSA Dosing". My Care Diagnostics.
- ^ Longley DB, Harkin DP, Johnston PG (May 2003). "5-fluorouracil: mechanisms of action and clinical strategies". Nat. Rev. Cancer 3 (5): 330–8. doi:10.1038/nrc1074. PMID 12724731.
- ^ "5-Fluorouracil derivatives: a patent review". Expert Opinion on Therapeutic Patents 22 (2): 107–123. February 2012. doi:10.1517/13543776.2012.661413. PMID 22329541.
- ^ Chu E (September 2007). "Ode to 5-Fluorouracil". Clinical Colorectal Cancer 6 (9): 609. doi:10.3816/CCC.2007.n.029.
- ^ National Academy of Sciences, Biographical Memoirs,80:135
- ^ Sneader W. (2005). Drug Discovery, p. 255.
- ^ Cohen, Seymour (30 January 2008). "50 years ago in cell biology: A virologist recalls his work on cell growth inhibition". The Scientist.
- ^ Heidelberger C, Chaudhuri NK, Danneberg P, et al. (March 1957). "Fluorinated pyrimidines, a new class of tumour-inhibitory compounds". Nature 179 (4561): 663–6. doi:10.1038/179663a0. PMID 13418758.
External links
- Cancerbackup.org.uk – Fluorouracil's use in cancer
