Fidaxomicin (OPT-80)   中文名称: 非达霉素

RNA polymerase

体外活性：Fidaxomicin 通过在形成起始转录的开放 RNAP-DNA 复合物之前与 DNA 模板-RNA 聚合酶 (RNAP) 复合物结合而发挥 RNA 聚合酶抑制剂的作用。因此它会抑制蛋白质的合成。结果，在易感生物体（例如艰难梭菌）中引发细胞凋亡。

fidaxomicin 对艰难梭菌对 90% 微生物的最低抑制浓度为 0.9978 至 2 μg/mL。如单剂量或多剂量后血浆浓度低于定量下限所示，非达霉素不被全身吸收。相比之下，非达霉素的粪便浓度要高得多并且具有浓度依赖性。 Cmax=2小时； Tmax = 5.2 纳克/毫升； AUC = 14 纳克·小时/毫升。 Fidaxomicin 被胃酸或肠微粒体水解成活性较低的代谢物 (OP-1118)。细胞色素酶系统不参与非达霉素的代谢。

Male Golden Syrian hamsters (80-100 g, Hamster model for pseudomembranous colitis)
0.2, 1, and 5 mg/kg
Orally, once a day for 5 days, beginning 8 h after infection

Absorption, Distribution and Excretion
Following oral administration of a single dose of 200 mg fidaxomicin in healthy adults, the Cmax of fidaxomicin and its main metabolite OP-1118 were 5.20 ± 2.81 ng/mL and 12.0 ± 6.06, respectively. The median Tmax of fidaxomicin was 2 hours. The systemic absorption of fidaxomicin following oral administration is minimal. In a food-effect study involving healthy adults in either with a high-fat meal versus under fasting conditions, the Cmax of fidaxomicin and OP-1118 were decreased by 21.5% and 33.4%, respectively; however, this effect is deemed to be clinically insignificant as the therapeutic action of fidaxomicin does not depend on drug concentrations in the systemic circulation.
Following oral administration, fidaxomicin is mainly excreted in feces. More than 92% of the dose was recovered in the faces as either the unchanged parent drug or metabolites in one study consisting of healthy adults receiving single doses of 200 mg and 300 mg of fidaxomicin. In another study of healthy adults, approximately 0.59% fo the oral dose (200 mg) administered was recovered in the urine as the main metabolite, OP-1118.
Fidaxomicin is mainly confined to the gastrointestinal tract when orally administered. There is limited information on the volume of distribution of fidaxomicin.
There is limited information on the clearance of fidaxomicin.

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Metabolism / Metabolites
Following oral administration, fidaxomicin is transformed to its main and pharmacologically active metabolite, OP-1118, via hydrolysis at the isobutyryl ester. As cytochrome enzymes are not involved in the metabolism of fidaxomicin, it is speculated that this biotransformation is mediated by gastric acid or enzymatic activity of intestinal microsomes.

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Biological Half-Life
Following oral administration of a single dose of 200 mg fidaxomicin in healthy adults, the elimination half-life of fidaxomicin was approximately 11.7 ± 4.80 hours.

Hepatotoxicity
In large clinical trials, therapy with fidaxomicin for ten days was associated with a low rate of serum aminotransferase elevations [1% to 3.2%], but rates with comparator agents such as vancomycin were similar [up to 2.7%]. There have been no reports of clinically apparent liver injury attributed to fidaxomicin. However, other oral macrolide antibiotics have been linked to many episodes of acute liver injury which can be severe and have resulted in fatalities. The onset of macrolide associated liver injury is typically 1 to 3 weeks after starting the drug and can arise after it is stopped. The injury is typically cholestatic, but can be mixed or hepatocellular. The hepatocellular cases are more likely to be severe and can result in acute liver failure. However, in most instances, recovery occurs within 4 to 8 weeks of withdrawal of the macrolide. No such cases, however, have been linked to use of fidaxomicin, which unlike the other macrolides is not absorbed orally.
Likelihood score: E (unlikely cause of clinically apparent liver injury).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
No information is available on the use of fidaxomicin during breastfeeding. Because it is poorly absorbed orally, it is not likely to reach the bloodstream of the infant or cause any adverse effects in breastfed infants.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Protein Binding
Since fidaxomicin has minimal systemic absorption following oral administration, there is limited information on the plasma protein binding profile of fidoxamicin.

[1]. Clin Infect Dis . 2012 Feb 15;54(4):568-74.

Pharmacodynamics
Fidaxomicin has a narrow-spectrum antibacterial profile, with potent bactericidal activity specifically against C. difficile. The minimum inhibitory concentration for 90% of organisms for fidaxomicin against _C. difficile_ ranged from 0.0078 to 2 μg/mL _in vitro_. The bactericidal activity of fidaxomicin is time-dependent. Other than _C. difficile_, fidaxomicin has moderate inhibitory activity against Gram-positive bacteria (_S. aureus_ and _Enterococcus spp._) and poor activity against normal colonic flora, including anaerobes and enteric Gram-negative bacilli. Isolates of _C. difficile_ that are resistant to rifamycins or other antimicrobial classes (such as cephalosporins, fluoroquinolones, clindamycin) were not shown to be cross-resistant to fidaxomicin.

C52H74CL2O18

1058.04

1056.425

C, 54.28; H, 5.04; F, 4.52; N, 13.33; O, 22.83

873857-62-6

10034073

White to off-white solid powder

1.3±0.1 g/cm3

1046.4±65.0 °C at 760 mmHg

586.7±34.3 °C

0.0±0.3 mmHg at 25°C

1.590

10.73

266.66

7

18

15

72

1970

14

ClC1=C(C(=C(C(=C1C([H])([H])C([H])([H])[H])C(=O)O[C@]1([H])[C@@]([H])(C([H])([H])[H])O[C@]([H])([C@]([H])([C@@]1([H])O[H])OC([H])([H])[H])OC([H])([H])C1C(=O)O[C@]([H])([C@@]([H])(C([H])([H])[H])O[H])C([H])([H])C([H])=C(C([H])([H])[H])C([H])=C(C([H])([H])[H])[C@@]([H])([C@]([H])(C([H])=C(C([H])([H])[H])[C@]([H])(C([H])([H])C([H])=C([H])C=1[H])O[H])C([H])([H])C([H])([H])[H])O[C@@]1([H])[C@]([H])([C@]([H])([C@@]([H])(C(C([H])([H])[H])(C([H])([H])[H])O1)OC(C([H])(C([H])([H])[H])C([H])([H])[H])=O)O[H])O[H])O[H])Cl)O[H] |c:63,70,81,93,96|

ZVGNESXIJDCBKN-UUEYKCAUSA-N

InChI=1S/C52H74Cl2O18/c1-13-30-22-26(6)33(56)18-16-15-17-31(23-66-51-45(65-12)42(61)44(29(9)67-51)69-49(64)35-32(14-2)36(53)39(58)37(54)38(35)57)48(63)68-34(28(8)55)20-19-25(5)21-27(7)43(30)70-50-41(60)40(59)46(52(10,11)72-50)71-47(62)24(3)4/h15-17,19,21-22,24,28-30,33-34,40-46,50-51,55-61H,13-14,18,20,23H2,1-12H3/b16-15+,25-19+,26-22+,27-21+,31-17+/t28-,29-,30+,33+,34+,40-,41+,42+,43+,44-,45+,46+,50-,51-/m1/s1

[(2R,3S,4S,5S,6R)-6-[[(3E,5E,8S,9E,11S,12R,13E,15E,18S)-12-[(2R,3S,4R,5S)-3,4-dihydroxy-6,6-dimethyl-5-(2-methylpropanoyloxy)oxan-2-yl]oxy-11-ethyl-8-hydroxy-18-[(1R)-1-hydroxyethyl]-9,13,15-trimethyl-2-oxo-1-oxacyclooctadeca-3,5,9,13,15-pentaen-3-yl]methoxy]-4-hydroxy-5-methoxy-2-methyloxan-3-yl] 3,5-dichloro-2-ethyl-4,6-dihydroxybenzoate

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

配方 1 中的溶解度: ≥ 2.5 mg/mL (2.36 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 25.0 mg/mL澄清DMSO储备液加入到400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: ≥ 2.5 mg/mL (2.36 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。