リファンピシン 化学特性,用途語,生産方法
外観
赤黄色～赤褐色, 結晶～粉末
性質
リファンピシンは黄橙色の結晶性粉末で、水への溶解性は低いものの、アルコールやアセトンには溶けやすいです。また、熱や光に不安定であるため、保存条件に注意必要です。
リファンピシンは、グラム陽性菌とグラム陰性菌の両方に対して広範な抗菌活性を示します。特に、結核菌に対して強力な効果を発揮します。
1. 作用機序
細菌のRNAポリメラーゼに対して作用し、細菌のDNAの転写を阻害します。これにより、細菌のタンパク質合成が抑制され、細菌の増殖が停止します。
2. 抗菌耐性
リファンピシンは耐性菌が出現しやすいため、通常は単剤ではなく、他の抗結核薬と組み合わせて使用されます。
3. 薬物動態
経口投与後に胃腸から速やかに吸収され、投与後約2〜4時間で血中濃度はがピークに達します。リファンピシンは肝臓で代謝され、尿中排泄されます。
4. 副作用
リファンピシンの一般的な副作用には、肝障害、黄疸、発疹、熱、消化器症状 (悪心、嘔吐、下痢) などがあります。重篤な副作用は稀ですが、アレルギーや肝臓障害が報告されています。
溶解性
メタノールにやや溶け易く、エーテルに溶けにくく、水またはエタノールに極めて溶けにくい。水、アセトニトリル、メタノール及びエタノール(95)に溶けにくい。
解説
3-[(4-methyl-1-piperazinyl)iminomethyl]rifamycin．C43H58N4O12(822.95)．リファンピンともいう．Streptomyces mediterraneiが産生する抗生物質リファマイシンSVの3-ホルミル誘導体に，1-アミノ-4-メチルピペラジンを縮合させた半合成品．リファンピシン, 赤橙色の板状晶．分解点183～188 ℃．λmax 237，255，334，475 nm(ε 33200，32100，27000，15400)．両性物質でpKa 1.7および7.9．水に安定で微溶，クロロホルムに易溶．細菌のRNA合成開始反応を阻害する．抗菌スペクトルは広く，結核治療の第一選択薬として使用されている．LD50 858 mg/kg(マウス，経口)．
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森北出版「化学辞典（第2版）
用途
リファンピン (rifampin) ともいう。製品名はリファジン?カプセル150mg(第一三共製造販売)。
放線菌の一種 Streptomyces mediterranei が生産するリファマイシンから半合成される。
結核やハンセン病の治療に用いられることがある。副作用としては肝機能障害などが挙げられる。
用途
細菌の DNA 依存性 RNA ポリ
メラーゼの阻害により、RNA 合成阻害作用を
示します。
用途
抗菌剤。
構造
リファンピシンは、独特で複雑な化学構造を持っています。基本骨格はナフタキノン骨格からなり、アンサマイシン環と呼ばれる大員環構造と、ピペラジン酸が結合した構造を指定ます。
アンサマイシン環はリファンピシンの脂溶性に関わり、細菌の細胞膜通過に寄与しています。また、ピペラジン酸部分はリファンピシンの活性部位であり、細菌のRNAポリメラーゼに対する親和性に重要な役割を果たしています。
効能
抗生物質, RNAポリメラーゼ阻害薬
商品名
リファジン (第一三共)
説明
Rifampicin is a semisynthetic derivative of rifamicin B, a macrolactam antibiotic and one
of more than five antibiotics from a mixture of rifamicins A, B, C, D, and E, which is called
a rifamicin complex, which is produced by actinomycetes Streptomyces mediteranei
(Nocardia mediteranei). It was introduced into medical practice in 1968. Synthesis of
rifampicin begins with an aqueous solution of rifamicin, which under the reaction conditions
is oxidized to a new derivative of rifamicin S (32.7.4), with the intermediate formation of rifamicin O (32.7.3). Reducing the quinone structure of this product with hydrogen using a
palladium on carbon catalyst gives rifamicin SV (32.7.5). The resulting product undergoes
aminomethylation by a mixture of formaldehyde and pyrrolidine, giving 3-pyrrolidinomethylrifamicin SV (32.7.6). Oxidizing the resulting product with lead tetracetate to an
enamine and subsequent hydrolysis with an aqueous solution of ascorbic acid gives
3-formylrifamicin SV (32.7.7). Reacting this with 1-amino-4-methylpiperazine gives the
desired rifampicin (32.7.8).
化学的特性
Red to Orange Crystalline Solid
使用
Rifampicin is used to treat Tuberculosis and Tuberculosis-related mycobacterial infections. It is widely used as an antipruritic agent in the autoimmune cholestatic liver disease, primary biliary cirrhosis (PBC). It has been shown to cause hepatitis.
適応症
Rifampin (300 to 450 mg daily) is very effective in relieving the pruritus of
primary biliary cirrhosis, by inhibiting hepatic bile uptake and stimulating
mixed-function oxidases. Liver enzymes should be monitored to detect druginduced
hepatitis.
定義
ChEBI: A member of the class of rifamycins that is a a semisynthetic antibiotic derived from Amycolatopsis rifamycinica (previously known as Amycolatopsis mediterranei and Streptomyces mediterranei)
抗菌性
It exhibits potent activity in vitro against Gram-positive cocci, including methicillin-resistant staphylococci (MIC <0.025–0.5 mg/L) and penicillinresistant pneumococci. Enterococci are less susceptible. Gram-positive bacilli, including Bacillus spp., Clostridium difficile, Corynebacterium spp. and Listeria monocytogenes, are highly susceptible (MIC 0.025–0.5 mg/L). The pathogenic Neisseria and Moraxella spp. are also highly susceptible.
Enteric Gram-negative bacteria are generally less sensitive (MIC 1–32 mg/L), but Bacteroides fragilis is highly susceptible. Among other Gram-negative bacilli, Haemophilus influenzae, H. ducreyi, Flavobacterium meningosepticum and Legionella spp. are highly susceptible (MIC <0.025–2 mg/L). Chlamydia trachomatis and Chlamydophila psittaci are inhibited by low concentrations (0.025–0.5 mg/L).
Most strains of M. tuberculosis, M. kansasii and M. marinum are inhibited by <0.01–0.1 mg/L, but M. fortuitum and members of the M. avium complex are resistant. M. leprae is highly sensitive.
Rifampicin is active against some eukaryotic parasites through inhibition of the prokaryote-like polymerase of kinetoplasts or mitochondria. Maturation of Plasmodium falciparum is inhibited by 2–10 mg/L; at higher concentrations Leishmania spp. are also inhibited.
High concentrations inhibit growth of a variety of poxviruses by interference with viral particle maturation; viral reverse transcriptase is unaffected.
獲得抵抗性
Most large bacterial populations contain resistant mutants, which readily emerge in the presence of the drug and can emerge during treatment. The mutation rate to resistance in Staph. aureus, Str. pyogenes, Str. pneumoniae, Esch. coli and Proteus mirabilis is about 10–7 and that to M. tuberculosis and M. marinum 10–9–10–10. Primary resistance in M. tuberculosis remained low for many years, but is increasing.
Resistance is of the one-step type, and several classes of mutants exhibiting different degrees of resistance can be selected by exposing a large population to a relatively low concentration of the drug. Some of these mutants may be susceptible to other rifamycin derivatives.
Resistance is due to a change in a single amino acid of the β subunit of DNA-dependent RNA polymerase, which no longer forms a stable complex with rifampicin. It is not transferable and there is no cross-resistance with any other antibiotic class. The susceptible strains of the gastrointestinal flora become rapidly resistant during rifampicin treatment without alteration in the flora composition, and revert to susceptibility within a few weeks of cessation of treatment.
一般的な説明
Eppendorf Tubes are the perfect option for working with medium-sized sample volumes!
- Maximum safety and stability for centrifugation up to 25,000 × g
- Conical bottoms
- Easier processing of samples up to 5.0 mL
- Higher yields in DNA isolation, prep of mastermixes and buffers, and safe cell and tissue lysis
- Transparent polypropylene, free of plasticizers, biocides or mold release agents
- Hinged lid for minimized sample evaporation during storage and incubation in a wide range of temperatures from -86°C to 80°C
使用用途
リファンピシンは抗生物質として、医療の現場で用いられています。具体的な適応症は、肺結核、非結核性抗酸菌症、ハンセン病などです。
作用機序は、リファンピシンが細菌のRNAポリメラーゼに作用して、細菌のRNA合成を阻害することにより、細菌のDNAの転写が阻害されます。それによって細菌のタンパク質合成が抑制され、薬剤の効果を発揮する仕組みです。
リファンピシンの主な副作用には、腎不全、間質性腎炎、ショック、アナフィラキシー、悪心、胃痛、嘔吐、食欲不振、下痢などが報告されています。
応用例（製薬）
Rifampin (USAN). Molecular weight: 822.95.
A semisynthetic derivative of rifamycin SV, available for oral administration or intravenous infusion and in several combined formulations with other antimycobacterial drugs. It is poorly soluble in water, but soluble in organic solvents.
作用機序
Rifampin is a semisynthetic macrocyclic antibiotic produced
from Streptomyces mediterranei. It is a large lipidsoluble
molecule that is bactericidal for both intracellular
and extracellular microorganisms. Rifampin binds
strongly to the β-subunit of bacterial DNA-dependent
RNA polymerase and thereby inhibits RNA synthesis.
Rifampin does not affect mammalian polymerases.
薬理学
Rifampin is well absorbed orally, and a peak serum concentration
is usually seen within 2 to 4 hours. Drug absorption is impaired if rifampin is given concurrently
with aminosalicylic acid or is taken immediately after a
meal. It is widely distributed throughout the body, and
therapeutic levels are achieved in all body fluids, including
cerebrospinal fluid. Rifampin is capable of inducing
its own metabolism, so its half-life can be reduced
to 2 hours within a week of continued therapy.
The deacetylated form of rifampin is active and undergoes
biliary excretion and enterohepatic recirculation.
Most of the drug is excreted into the GI tract and a
small amount in the urine.Moderate dose adjustment is
required in patients with underlying liver disease.
臨床応用
Tuberculosis (in combination with other antituberculosis agents; see Ch. 58)
Leprosy (in combination with other antileprotic agents; see Ch. 57)
Serious infection with multiresistant staphylococci and pneumococci (in combination with a glycopeptide)
Elimination of nasopharyngeal carriage of Neisseria meningitidis and H. influenzae.
副作用
Rifampicin is relatively non-toxic, even when administered for a long period (as in the treatment of tuberculosis). However, several unwanted effects, including pink staining of soft contact lenses, are associated with its use. Other reactions can be divided into those associated with daily or intermittent administration, and those found only with intermittent therapy.
安全性プロファイル
Suspected carcinogen with experimental neoplastigenic and teratogenic data. Poison by intraperitoneal and intravenous routes. Moderately toxic to humans by ingestion. Moderately experimentally toxic by ingestion and subcutaneous routes. Human systemic effects by ingestion: conjunctiva irritation, iritis (inflammation of the iris), other eye effects, dermatitis. Experimental reproductive effects. Human mutation data reported. When heated to decomposition it emits toxic fumes of NOx.
製造方法
リファンピシン の製造方法
リファンピシンは、もともとストレプトマイセス属の放線菌（特にStreptomyces mediterranei）から分離された天然化合物ですが、その後の需要と合成技術の進歩によって、さまざまな合成法が開発されました。現在、工業的に用いられている製造方法には、生物学的方法と化学的な半合成の両方があります。
最も一般的なのはS. mediterraneiに代表される菌株の放線菌を培養し、生成されたリファンピシンを培地から抽出・精製する方法です。これらの菌株を、リファンピシン産生を促進するための適切な培地で通常は28～30℃、pH6～8の条件下で数日間培養し、培地中に溶出したリファンピシンを分離・回収します。生成にはゲル濾過やイオン交換といったクロマトグラフィーが一般的で、再結晶化が用いられる場合もあります。
純化方法
This macrolide antibiotic crystallises form Me2CO in red-orange plates. It has UV max at 237, 255, 334, and 475nm ( 33,200, 32,100, 27,000 and 15,400) at pH 7.38. It is stable in Me2SO and H2O and is freely soluble in most organic solvents but slightly soluble in H2O at pH <6. [Binda et al. Arzneim.-Forsch 21 1907 1971.] It inhibits cellular RNA synthesis without affecting DNA [Calvori et al. Nature 207 417 1965].
リファンピシン 上流と下流の製品情報
原材料
準備製品