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a crystalline compound used as an antithyroid drug in the treatment of goiter

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2015/08/24 22:54:38」(JST)

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Propylthiouracil (PTU) or 6-n-propylthiouracil (PROP) is a thiouracil-derived drug used to treat hyperthyroidism (including Graves' disease) by decreasing the amount of thyroid hormone produced by the thyroid gland.^[1] Its notable side effects include a risk of agranulocytosis and aplastic anemia.

On 3 June 2009, the FDA published an alert "notifying healthcare professionals of the risk of serious liver injury, including liver failure and death, with the use of propylthiouracil."^[2] As a result, propylthiouracil is no longer recommended in non-pregnant adults and in children as the front line antithyroid medication.^[3]

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.[3]

History

It was approved by the US Food and Drug Administration in 1947.

Mechanism of action

Central

PTU inhibits the enzyme thyroperoxidase, which normally acts in thyroid hormone synthesis by oxidizing the anion iodide (I⁻) to iodine (I⁰), facilitating iodine's addition to tyrosine residues on the hormone precursor thyroglobulin. This is one of the essential steps in the formation of thyroxine (T4).^[4]

PTU does not inhibit the action of the sodium-dependent iodide transporter located on follicular cells' basolateral membranes. Inhibition of this step requires competitive inhibitors, such as perchlorate and thiocyanate.

Peripheral

PTU also acts by inhibiting the enzyme 5'-deiodinase (tetraiodothyronine 5' deiodinase), which converts T₄ to the active form T₃. (This is in contrast to methimazole, which shares propylthiouracil's central mechanism, but not its peripheral one.)

Pharmacokinetics

Administration is oral, with peak serum concentrations occurring in one hour, and actively concentrated to the thyroid gland. Depending on several patient variables, however, euthyroid status may not be achieved until 2–4 months after treatment initiation. Of note, the drug is approximately 70% protein-bound and significantly ionized at normal physiologic pH, while the antithyroid agent methimazole is substantially less protein bound. However both are equally transferred across the placenta.^[5]

The plasma half-life is one hour and is not altered appreciably by the thyroid status of the patient. Due to the concentration in the thyroid, however, dosing intervals may last 8 hours or longer. Less than 10% of the drug is excreted unchanged, with the remaining fraction undergoing extensive hepatic metabolism via glucuronidation.

Side effects

One possible side effect is agranulocytosis,^[6] a decrease of white blood cells in the blood. Symptoms and signs of agranulocytosis include infectious lesions of the throat, the gastrointestinal tract, and skin with an overall feeling of illness and fever. A decrease in blood platelets (thrombocytopenia) also may occur. Since platelets are important for the clotting of blood, thrombocytopenia may lead to problems with excessive bleeding. Side effects are suspected and the drug is sometimes discontinued if the patient complains of recurrent episodes of sore throat.

A more life-threatening side effect is sudden, severe, fulminant liver failure resulting in death or liver transplantation, which occurs in up to 1 in 10,000 people taking propylthiouracil. Unlike agranulocytosis which most commonly occurs in the first three months of therapy, this side effect may occur at any time during treatment.^[3]

Propylthiouracil is generally well tolerated, with side effects occurring in one of every 100 patients.^{[citation needed]} The most common side effects are related to the skin, and include rash, itching, hives, abnormal hair loss, and skin pigmentation.^{[citation needed]} Other common side effects are swelling, nausea, vomiting, heartburn, loss of taste, joint or muscle aches, numbness and headache, allergic reactions, and hair whitening.^{[citation needed]}

Propylthiouracil in pregnancy

Propylthiouracil is classified as Drug Class D in pregnancy. Class D signifies there is positive evidence of human fetal risk. Maternal benefit may outweigh fetal risk in life-threatening situations.^[7] PTU is preferred over methimazole (which is also a class D) only in the first trimester of pregnancy and in woman who may become pregnant because of the increased risk of teratogenicity of Methimazole during critical organogenesis. In the second and third trimester, this risk is diminished and methimazole is preferred to avoid the risk of liver complications from PTU in the mother.^[3]

The primary effect on the fetus from transplacental passage of PTU is the production of a mild hypothyroidism when the drug is used close to term. This usually resolves within a few days without treatment. The hypothyroid state may be observed as a goiter in the newborn, and is the result of increased levels of fetal pituitary thyrotropin.^[8] The incidence of fetal goiter after PTU treatment in reported cases is approximately 12%.^[9]

Chemical synthesis

Propylthiouracil can be prepared from ethyl 3-oxohexanoate and thiourea.^[10]

References

^ Nakamura H, Noh JY, Itoh K, Fukata S, Miyauchi A, Hamada N (June 2007). "Comparison of methimazole and propylthiouracil in patients with hyperthyroidism caused by Graves' disease". The Journal of Clinical Endocrinology and Metabolism 92 (6): 2157–62. doi:10.1210/jc.2006-2135. PMID 17389704.
^ "Propylthiouracil (PTU)-Induced Liver Failure". FDA. Retrieved 2009-05-03.
^ ^a ^b ^c Bahn RS, Burch HS, Cooper DS et al. (July 2009). "The Role of Propylthiouracil in the Management of Graves' Disease in Adults: report of a meeting jointly sponsored by the American Thyroid Association and the Food and Drug Administration". Thyroid 19 (7): 673–4. doi:10.1089/thy.2009.0169. PMID 19583480.
^ Boron, WF & Boulpaep, EL. 2005. Medical Physiology, Updated Edition. Elsevier Saunders, Philadelphia, PA
^ Abalovich M, Amino N, Barbour LA et al. (August 2007). "Management of thyroid dysfunction during pregnancy and postpartum: an Endocrine Society Clinical Practice Guideline". J. Clin. Endocrinol. Metab. 92 (8 Suppl): S1–47. doi:10.1210/jc.2007-0141. PMID 17948378.
^ Cho YY, Shon HS, Yoon HD (December 2005). "Management of a pregnant patient with Graves' disease complicated by propylthiouracil induced agranulocytosis". The Korean journal of internal medicine 20 (4): 335–8. PMID 16491833.
^ "propylthiouracil". Online.epocrates.com. Retrieved 2013-11-29.
^ Fumarola, A; Di Fiore, A; Dainelli, M; Grani, G; Carbotta, G; Calvanese, A (Jun 2011). "Therapy of hyperthyroidism in pregnancy and breastfeeding.". Obstetrical & gynecological survey 66 (6): 378–85. doi:10.1097/OGX.0b013e31822c6388. PMID 21851752.
^ "Propylthiouracil: Drug safety during pregnancy and breastfeeding". Drugsafetysite.com. Retrieved 2013-11-29.
^ Anderson, George W.; Halverstadt, I. F.; Miller, Wilbur H.; Roblin, Richard O. (1945). "Studies in Chemotherapy. X. Antithyroid Compounds. Synthesis of 5- and 6- Substituted 2-Thiouracils from β-Oxoesters and Thiourea". Journal of the American Chemical Society 67 (12): 2197–2200. doi:10.1021/ja01228a042.
^ http://www.chemspider.com/Chemical-Structure.2297424.html?rid=5e204a5f-8bb8-43b0-945a-dec7e90839e8

External links

"Clinical Pharmacology Online Database".

UpToDate Contents

全文を閲覧するには購読必要です。 To read the full text you will need to subscribe.

1. チオナミドによるバセドウ病（グレーブス病）の治療 thionamides in the treatment of graves disease
2. チオナミドの薬理学および毒性 pharmacology and toxicity of thionamides
3. 妊娠中の甲状腺機能亢進症：治療 hyperthyroidism during pregnancy treatment
4. 妊娠していない成人におけるグレーブス甲状腺機能亢進症：治療の概要 graves hyperthyroidism in nonpregnant adults overview of treatment
5. アルコール性脂肪性肝疾患およびアルコール性肝硬変の予後および治療 prognosis and management of alcoholic fatty liver disease and alcoholic cirrhosis

English Journal

The propylthiouracil dilemma.

Glinoer D, Cooper DS.SourceaDivision of Endocrinology, Faculty of Medicine, Hospital Saint Pierre, University of Brussels (ULB), Brussels, Belgium bDivision of Endocrinology and Metabolism, The Johns Hopkins School of Medicine, Baltimore, Maryland, USA.
Current opinion in endocrinology, diabetes, and obesity.Curr Opin Endocrinol Diabetes Obes.2012 Oct;19(5):402-7.
PURPOSE OF REVIEW: To bring to the attention of healthcare professionals the additional information on propylthiouracil (PTU)-related hepatotoxicity, based on a reanalysis of medical files reported to the Food and Drug Administration (1982-2008) for acute liver failure in PTU-treated hyperthyroid pa
PMID 22820213

Role of TSH in the Spontaneous Development of Asymmetrical Thyroid Carcinoma in Mice with a Targeted Mutation in a Single Allele of the Thyroid Hormone-β Receptor.

Zhao L, Zhu X, Won Park J, Fozzatti L, Willingham M, Cheng SY.SourceLaboratory of Molecular Biology, National Cancer Institute, 37 Convent Drive, Room 5128, Bethesda, Maryland 20892-4264. chengs@mail.nih.gov.
Endocrinology.Endocrinology.2012 Oct;153(10):5090-100. Epub 2012 Aug 23.
Mutations of the thyroid hormone receptor-β gene (THRB) cause resistance to thyroid hormone (RTH). A mouse model of RTH harboring a homozygous thyroid hormone receptor (TR)-β mutation known as PV (Thrb(PV/PV) mouse) spontaneously develops follicular thyroid cancer (FTC). Similar to RTH patients wi
PMID 22919057

Japanese Journal

治療抗甲状腺薬で治療するには (特集バセドウ病の診療に必要な知識)

伊藤光泰
内分泌・糖尿病・代謝内科 32(5), 438-443, 2011-05
NAID 40018905219

プロピルチオウラシルによるANCA関連血管炎の1例--Buerger病合併例 (特集血管炎・血行障害)

大野志保,中村晃一郎,倉持朗 [他]
皮膚科の臨床 53(2), 209-213, 2011-02
NAID 40018707384

Related Pictures

★リンクテーブル★

リンク元	「薬理学」「抗甲状腺薬」「プロピルチオウラシル」「チアマゾール」「PTU」
拡張検索	「propylthiouracilum」

「薬理学」

Propylthiouracil
Systematic (IUPAC) name
	6-propyl-2-sulfanylpyrimidin-4-one
Clinical data
AHFS/Drugs.com	monograph
MedlinePlus	a682465
Pregnancy; category	D;
Legal status	℞ (Prescription only);
Routes of; administration	Oral
Pharmacokinetic data
Bioavailability	80%-95%
Metabolism	?
Biological half-life	2 hours
Excretion	?
Identifiers
CAS Registry Number	51-52-5
ATC code	H03BA02
PubChem	CID: 657298
IUPHAR/BPS	6650
DrugBank	DB00550
ChemSpider	571424
UNII	721M9407IY
KEGG	D00562
ChEBI	CHEBI:8502
ChEMBL	CHEMBL1518
Chemical data
Formula	C7H10N2OS
Molecular mass	170.233 g/mol
	SMILES S=C1N/C(=C\C(=O)N1)CCC ;
	InChI InChI=1S/C7H10N2OS/c1-2-3-5-4-6(10)9-7(11)8-5/h4H,2-3H2,1H3,(H2,8,9,10,11) ; Key:KNAHARQHSZJURB-UHFFFAOYSA-N ;
(what is this?) (verify)

　　[★]

英: pharmacology
関: drug entries

定義

生物系と化学物質の選択的な相互作用を研究する学問 (SPC.2)

生物系と薬の相互作用

薬の生物系に対する相互作用：薬理作用 <-化学の視点
生物系の薬に対する相互作用：薬物動態 <-生物の視点

薬品の命名

Ending of the drug name	Category	Example
～afil	Erectile dysfunction	sildenafil
～ane	Inhalatinal general anesthetic	halothane
～azepam	Benzodiaizepine	diazepam
～azine	Phenothiazine (neuroleptic, antiemetic)	chlorpromazine
～azole	Ailtifungal	ketoconazole
～barbital	Barbiturate	phenobarbital
～caine	Local anesthetic	lidocaine
～cillin	Penicillin	methicillin
～cycline	Antibiotic, protein syntlesis inhibitor	tetracycline
～ipramine	TCA	iimipramine
～navir	Protease inhibitor	saquinavir
～olol	β-antagonist	propranolol
～operidol	Butyrophenone ( neuroleptic )	haloperidol
～oxin	Cardiac glycoside ( inotropic agent )	digoxin
～phylline	Methylxanthine	theophylline
～pril	ACE inhibitor	captopril
～terol	β₂ agonist	albuterol
～tidine	H₂ antagonist	cimtidine
～triptyline	TCA	amitriptyline
～tropine	Pituitary hormone	somatotropine
～zosin	a₁ antagonist	prazosin

薬一覧

薬物代謝

薬理動態

神経伝達物質

貧血治療薬

甲状腺関連物質

甲状腺ホルモン製剤

レボチロキシン levothyroxine
リオチニシン liothyronine

抗甲状腺薬

痛風治療薬

痛風発作予防薬

コルヒチン colchicine

尿酸排泄促進薬

尿酸生成抑制薬

アロプリノール allopurinol

「抗甲状腺薬」

　　[★]

英: antithyroid drug
同: 甲状腺阻害薬
関: 甲状腺中毒症、薬理学、甲状腺、甲状腺ホルモン

種類

チアミド系の化合物が用いられる(SPC.323)

作用機序

甲状濾胞内に能動的に取り込まれ、濾胞内でヨードの有機化と縮合を抑制
甲状腺濾胞内に浸潤しているリンパ球の自己抗体産生を抑制

副作用

チアミド系化合物の副作用

皮疹(2-3週後)が最多、甲状腺機能低下症、甲状腺腫、まれに白血球減少症/顆粒球減少症(治療開始後3-12週)

副作用に対する対処

無顆粒球症

症状：突然の咽頭痛、発熱
処置：

抗甲状腺薬の中止。副腎皮質ホルモン、抗菌薬、輸血、G-CSF (医学辞書改変)
無顆粒球症(好中球＜500/ul)と判断されたらすぐに抗甲状腺薬の中止。

薬物動態の比較

文献不明

	チアマゾール thiamazole メチマゾール methimazole methylmercaptoimidazole MMI	プロピルチオウラシル PTU
商品名	メルカゾール(5mg/錠)	プロパジール(50mg/錠)
薬効	13-14	1
初回量	30-45 mg	300-600 mg
維持量	5-10 mg	50-200 mg
血中半減期	約6時間	約2.5時間
作用持続時間	24時間	4-8時間
吸収	ほぼ100%	ほぼ100%
アルブミン結合	5%以下	約80%
末梢作用	なし	T4→T3への変換を抑制
作用発現(T4正常化)	1-2ヶ月	2-3ヶ月
胎盤移行	多い	少ない
乳汁移行	多い	ほとんどなし
尿中排泄	48時間で約70%	24時間で約80%
肝・腎不全時	代謝不変	代謝低下

SPC.1528

	チアマゾール	プロピルチオウラシル
血漿タンパクとの結合	結合しない	0.75
血漿半減期	4?6時間	75分
分布容積	40 liters	20 liters
甲状腺での濃縮	濃縮	濃縮
重症な肝臓病患者での代謝	減少	普通
重症な腎臓病患者での代謝	普通	普通
投与頻度	1-2回/日	1-4回/日
胎盤の通過	低	低
母乳への移行	低	低

参考

uptodate

1. [charged] チオナミドによるバセドウ病（グレーブス病）の治療 - uptodate [1]
2. [charged] チオナミドの薬理学および毒性 - uptodate [2]
3. [charged] 患者情報：抗甲状腺剤 - uptodate [3]

「プロピルチオウラシル」

　　[★]

英: propylthiouracil, PTU
ラ: propylthiouracilum
商: チウラジール、プロパジール
関: 薬理学、甲状腺、抗甲状腺薬

分類

抗甲状腺薬

薬理作用

1. 甲状腺濾胞細胞内に取り込まれ、甲状腺濾胞においてペルオキシダーゼの活性を阻害し、甲状腺ホルモンの合成を抑制

ペルオキシダーゼは濾胞内でO₂からH₂O₂を生成し、H₂O₂によりI^-がI^･となりサイログロブリン上のチロシンに付加反応を起こす

この阻害作用はチアマゾールも示し、チアマゾールの方が薬効が高い(より少量で作用する)

2. 末梢(肝、腎)でT₄からT₃へ変換を抑制する

肝、腎、甲状腺にはtype I iodothyronine 5'-deiodinaseが存在し、T₄からT₃へ変換している。

副作用

皮膚の発疹：よく見られる
甲状腺機能低下症
甲状腺腫
顆粒球減少症 (0.2%) (SPC.323)

GOO.1529

肝機能の異常は高投与量でみられるかもしれない
稀：発熱、肝炎、腎炎、血管炎(ANCAと関連か？)
antineutrophilic cytoplasmic antibody(ANCA)はプロピルチオウラシル投与患者の50%に見られる

(別の資料では、20%の患者がANCA陽性)

ANCA陽性腎炎と関連？

「チアマゾール」

　　[★]

英: thiamazole
ラ: thiamazolum
同: メチマゾール methimazole、メルカプトメチルイミダゾール mercaptomethylimidazole MMI
商: メルカゾール、Tapazole
関: 薬理学、甲状腺機能亢進症。プロピルチオウラシル propylthiouracil PTU

抗甲状腺薬

thioamide系薬

作用機序

薬理作用

甲状腺濾胞細胞内に取り込まれ、甲状腺濾胞においてペルオキシダーゼの活性を阻害し、甲状腺ホルモンの合成を抑制

ペルオキシダーゼは濾胞内でO₂からH₂O₂を生成し、H₂O₂によりI^-がI^･となりサイログロブリン上のチロシンの3位or5位につく

プロピルチオウラシルのようにT₄→T₃の変換を阻害する作用無し

動態

胎盤を通過
乳汁中に分泌　→　妊婦には投与しない方がよい

適応

注意

禁忌

副作用

皮膚の発疹：よく見られる
甲状腺機能低下症
甲状腺腫
顆粒球減少症 (0.2%) (SPC.323)

「PTU」

　　[★] プロピルチオウラシル propylthiouracil

「propylthiouracilum」

　　[★] プロピルチオウラシル

[pmid17389704-1] Nakamura H, Noh JY, Itoh K, Fukata S, Miyauchi A, Hamada N (June 2007). "Comparison of methimazole and propylthiouracil in patients with hyperthyroidism caused by Graves' disease". The Journal of Clinical Endocrinology and Metabolism 92 (6): 2157–62. doi:10.1210/jc.2006-2135. PMID 17389704.

[2] "Propylthiouracil (PTU)-Induced Liver Failure". FDA. Retrieved 2009-05-03.

[FDA_PTU_Guidelines-3] Bahn RS, Burch HS, Cooper DS et al. (July 2009). "The Role of Propylthiouracil in the Management of Graves' Disease in Adults: report of a meeting jointly sponsored by the American Thyroid Association and the Food and Drug Administration". Thyroid 19 (7): 673–4. doi:10.1089/thy.2009.0169. PMID 19583480.

[4] Boron, WF & Boulpaep, EL. 2005. Medical Physiology, Updated Edition. Elsevier Saunders, Philadelphia, PA

[ESCPG-5] Abalovich M, Amino N, Barbour LA et al. (August 2007). "Management of thyroid dysfunction during pregnancy and postpartum: an Endocrine Society Clinical Practice Guideline". J. Clin. Endocrinol. Metab. 92 (8 Suppl): S1–47. doi:10.1210/jc.2007-0141. PMID 17948378.

[pmid16491833-6] Cho YY, Shon HS, Yoon HD (December 2005). "Management of a pregnant patient with Graves' disease complicated by propylthiouracil induced agranulocytosis". The Korean journal of internal medicine 20 (4): 335–8. PMID 16491833.

[Epocrates-7] "propylthiouracil". Online.epocrates.com. Retrieved 2013-11-29.

[8] Fumarola, A; Di Fiore, A; Dainelli, M; Grani, G; Carbotta, G; Calvanese, A (Jun 2011). "Therapy of hyperthyroidism in pregnancy and breastfeeding.". Obstetrical & gynecological survey 66 (6): 378–85. doi:10.1097/OGX.0b013e31822c6388. PMID 21851752.

[Drugs_in_Pregnancy_and_Lactation-9] "Propylthiouracil: Drug safety during pregnancy and breastfeeding". Drugsafetysite.com. Retrieved 2013-11-29.

[10] Anderson, George W.; Halverstadt, I. F.; Miller, Wilbur H.; Roblin, Richard O. (1945). "Studies in Chemotherapy. X. Antithyroid Compounds. Synthesis of 5- and 6- Substituted 2-Thiouracils from β-Oxoesters and Thiourea". Journal of the American Chemical Society 67 (12): 2197–2200. doi:10.1021/ja01228a042.

[11] ttp://www.chemspider.com/Chemical-Structure.2297424.html?rid=5e204a5f-8bb8-43b0-945a-dec7e90839e8

匿名

検索

案内

propylthiouracil

WordNet

Wikipedia preview

wiki en

Contents

History

Mechanism of action

Central

Peripheral

Pharmacokinetics

Side effects

Propylthiouracil in pregnancy

Chemical synthesis

See also

References

External links

UpToDate Contents

English Journal

Japanese Journal

Related Links

Related Pictures

★リンクテーブル★

「薬理学」

定義

生物系と薬の相互作用

関連分野

薬品の命名

薬一覧

薬物代謝

薬理動態

神経伝達物質

神経筋接合部遮断薬(筋弛緩薬)

交感神経作動薬

交感神経遮断薬

副交感神経作動薬

副交感神経遮断薬

貧血治療薬

甲状腺関連物質

痛風治療薬

「抗甲状腺薬」

種類

作用機序

副作用

副作用に対する対処

薬物動態の比較

参考

uptodate

「プロピルチオウラシル」

分類

薬理作用

副作用

GOO.1529

「チアマゾール」

作用機序

薬理作用

動態

適応

注意

禁忌

副作用

「PTU」

「propylthiouracilum」