-
外観
白色~わずかにうすい黄色、結晶~粉末
-
溶解性
DMSOに溶解 (20mg/ml), エタノールに溶解 (20mg/ml)熱エタノール及び熱アセトンに溶け、熱水にほとんど溶けない。メタノールにやや溶けやすく、エタノール(99.5)にやや溶けにくく、水にほとんど溶けない。
-
用途
ケトコナゾール(Ketoconazole)とは真菌症の治療に使用されるイミダゾール系合成抗真菌薬の一つである。白癬、カンジダ症、癜風等の治療に用いられる。
全身投与には通常、より毒性の低いトリアゾール系抗真菌薬であるフルコナゾールやイトラコナゾール(英語版)が用いられる。
ケトコナゾールの作用には他に糖質コルチコイド(英)の生合成を抑制する作用があるので、抗うつ薬への応用の可能性について研究された事がある。
ケトコナゾールの外用剤は通常、皮膚、粘膜の真菌感染症(白癬、カンジダ症、癜風等)に処方される。そのほか、真菌の一種Malassezia furfur が関係する頭垢や体部脂漏性湿疹に対して皮膚の菌を抑えるためにも使用される。
-
用途
薬物代謝の研究、創薬の研究用。
-
用途
ケトコナゾールの作用には他に糖質コルチコイド(英)の生合成を抑制する作用があるので、抗うつ薬への応用の可能性について研究された事がある。 ケトコナゾールの外用剤は通常、皮膚、粘膜の真菌感染症(白癬、カンジダ症、癜風等)に処方される。そのほか、真菌の一種Malassezia furfur が関係する頭垢や体部脂漏性湿疹に対して皮膚の菌を抑えるためにも使用される。
-
用途
イミダゾール系抗菌剤です。
トクローム P450 3A4 の阻害作用を示しま
す。
-
効能
抗真菌薬, エルゴステロール合成阻害薬
-
商品名
ケトコナゾール (岩城製薬); ケトコナゾール (岩城製薬); ニゾラール (ヤンセンファーマ); ニゾラール (ヤンセンファーマ)
-
確認試験
本品の表示量に従い「ケトコナゾール」10mgに対
応する量をとり,メタノールを加えて10mLとし,試料溶液
とする.別にケトコナゾール10mgをメタノール10mLに溶
かし,標準溶液とする.これらの液につき,薄層クロマトグ
ラフィー〈2.03〉により試験を行う.試料溶液及び標準溶液
5μLずつを薄層クロマトグラフィー用シリカゲル(蛍光剤入
り)を用いて調製した薄層板にスポットする.次に酢酸エチ
ル/ヘキサン/メタノール/水/アンモニア水(28)混液
(40:40:30:2:1)を展開溶媒として約10cm展開した後,
薄層板を風乾する.これに紫外線(主波長254nm)を照射する
とき,試料溶液から得た主スポット及び標準溶液から得たス
ポットのR f値は等しい.
-
定量法
本品を乾燥し,その約0.2gを精密に量り,2-ブタノ
ン/酢酸(100)混液(7:1)70mLに溶かし,0.1mol/L過塩素酸
で滴定〈2.50〉する(電位差滴定法).同様の方法で空試験を行
い,補正する.
-
純度試験
(1) 重金属〈1.07〉 本品1.0gをとり,第2法により操作し,
試験を行う.比較液には鉛標準液1.0mLを加える(10ppm以下).
(2) 類縁物質 本品0.10gをメタノール10mLに溶かし,
試料溶液とする.この液5mLを正確に量り,メタノールを
加えて正確に100mLとする.この液1mLを正確に量り,メ
タノールを加えて正確に10mLとし,標準溶液とする.試料
溶液及び標準溶液10μLずつを正確にとり,次の条件で液体
クロマトグラフィー〈2.01〉により試験を行う.それぞれの
液の各々のピーク面積を自動積分法により測定するとき,試
料溶液のケトコナゾール以外のピークの面積は,標準溶液の
ケトコナゾールのピーク面積の2/5より大きくない.また,
試料溶液のケトコナゾール以外のピークの合計面積は,標準
溶液のケトコナゾールのピーク面積より大きくない.
(3) 残留溶媒 別に規定する.
-
乾燥減量
0.5%以下(1g,105℃,4時間).
-
使用上の注意
取り扱う場合は、保護眼鏡、保護手袋及び保護マスクを用いる。
-
説明
Ketoconazole (Nizoral), an orally effective broadspectrum antifungal agent, blocks hydroxylating enzyme systems by interacting with cytochrome P450 at the heme iron site to inhibit steroid and/or androgen synthesis in adrenals, gonads, liver, and kidney. The most sensitive site of action appears to be the C17-20 lyase reaction involved in the formation of sex steroids. This explains the greater suppressibility of testosterone production than with cortisol. Cholesterol side-chain cleavage and 11β/18-hydroxylase are secondary sites of inhibition.
-
化学的特性
White or almost white powder.
-
使用
Ketoconazole is used to treat candidiasis, chronic mucocutaneous candidiasis, oral thrush, candiduria, blastomycosis, coccidioidomycosis, histoplasmosis, chromomycosis, and paracoccidioidomycosis. Ketoconazole is an antifungal agent.
-
適応症
Ketoconazole (Nizoral) is approved for treating dermatophyte infections unresponsive to griseofulvin and for patients unable to tolerate that drug. It is a broad-spectrum antifungal agent that in very high doses inhibits several steps in the biosynthesis of both adrenal and gonadal steroids. While the normal antifungal dose is 200 mg/day, testosterone biosynthesis in both the adrenal and testis is completely abolished by doses of 800 to 1,600 mg/day. This drug is used most commonly for large virilizing adrenal tumors that cannot be surgically removed.
-
世界保健機関(WHO)
Ketoconazole, an imidazole antifungal agent, was introduced in
1978 for the topical and systemic treatment of a wide variety of fungal infections.
Its use by mouth has been associated with hepatotoxicity, including cases of
hepatitis, which have usually been reversible on discontinuation of the drug, but
some fatalities have also occurred. Ketoconazole is widely marketed.
-
抗菌性
The spectrum includes dermatophytes, some dimorphic fungi
and Candida spp.
-
獲得抵抗性
Resistance has been documented in patients treated for
chronic mucocutaneous candidosis and AIDS patients with
oropharyngeal or esophageal candidosis. Some fluconazoleresistant
C. albicans and C. glabrata are cross-resistant to
ketoconazole.
-
一般的な説明
Ketoconazole is an imidazole antifungal agent administered through topical or oral means. It is used for the treatment of chronic mucocutaneous candidiasis, fungal infections of the gastro-intestinal tract, dermatophyte infections, systemic infections, and fungal infections in immuno-compromised patients.
-
応用例(製薬)
A synthetic dioxolane imidazole available for oral and topical
use.
-
生物活性
Antifungal agent; potent inhibitor of cytochrome P450c17.
-
作用機序
Ketoconazole has little effect on Aspergillus or Cryptococcus. Ketoconazole is highly dependent on low stomach pH for absorption, and antacids or drugs that raise stomach pH will lower the bioavailability of ketoconazole. As with other azoles, it is extensively metabolized by microsomal enzymes. All the metabolites are inactive. Evidence that CYP3A4 plays a significant role in metabolism of ketoconazole is that coadministration of CYP3A4 inducers, such as phenytoin, carbamazepine, and rifampin, can cause as much as a 50% reduction in levels of ketoconazole.
-
薬物動態学
Oral absorption: Variable
Cmax 400 mg oral: c. 5–6 mg/L after 2 h
Plasma half-life: 6–10 h
Volume of distribution: 0.36 L/kg
Plasma protein binding: >95%
It is erratically absorbed after oral administration. Absorption
is favored by an acid pH. Food delays absorption, but does not
significantly reduce the peak serum concentration. Absorption
is reduced if it is given with compounds that reduce gastric
acid secretion. Penetration into CSF is generally
poor
and unreliable, although effective concentrations have been recorded with high doses in some cases of active meningitis. It
is extensively metabolized by the liver, and the metabolites are
excreted in the bile. Less than 1% of an oral dose is excreted
unchanged in the urine.
-
臨床応用
Ketoconazole remains useful in the treatment of cutaneous
and mucous membrane dermatophyte and yeast
infections, but it has been replaced by the newer triazoles
in the treatment of most serious Candida infections
and disseminated mycoses. Ketoconazole is usually
effective in the treatment of thrush, but fluconazole
is superior to ketoconazole for refractory thrush.
Widespread dermatophyte infections on skin surfaces
can be treated easily with oral ketoconazole when the
use of topical antifungal agents would be impractical.
Treatment of vulvovaginal candidiasis with topical imidazoles
is less expensive.
-
副作用
Nausea, vomiting, and anorexia occur commonly with
ketoconazole, especially when high doses are prescribed.
Epigastric distress can be reduced by taking ketoconazole
with food. Pruritis and/or allergic dermatitis
occurs in 10% of patients. Liver enzyme elevations during
therapy are not unusual and are usually reversible.
Severe ketoconazole-associated hepatitis is rare.
At high doses, ketoconazole causes a clinically significant
reduction in testosterone synthesis and blocks
the adrenal response to corticotropin. Gynecomastia,
impotence, reduced sperm counts, and diminished libido
can occur in men, and prolonged drug use can result
in irregular menses in women. These hormonal effects
have led to the use of ketoconazole as a potential
adjunctive treatment for prostatic carcinoma.
-
代謝
Ketoconazole is extensively degraded by the liver, and very little active
drug is excreted in either the urine or bile; the dose need not be modified
for renal insufficiency. Adverse reactions to topical ketoconazole are very
rare.
-
予防処置
Both rifampin and isoniazid lower plasma ketoconazolelevels, and concomitant administration should be avoided.Phenytoin serum levels should be monitored closelywhen ketoconazole is prescribed.Ketoconazole causes increasesin serum concentrations of warfarin, cyclosporine,and sulfonylureas. Because of its ability to increase serumcyclosporine levels, ketoconazole has been given to cyclosporine-dependent cardiac transplant recipients to reducethe dose of cyclosporine needed and as a cost-savingmeasure.