β-lactam; bacterial cell wall synthesis

头孢洛林酯（TAK-599）是抗甲氧西林耐药金黄色葡萄球菌（MRSA）头孢菌素2a （T-91825）的新型n-膦前药，对青霉素结合蛋白（PBP） 2′(IC（50）具有高亲和力；0.90微克/毫升)，并显示出有效的体外抗MRSA活性(MIC抗MRSA N133；1.56微克/毫升)，与万古霉素（1.56微克/毫升）相当。［１］

Ceftaroline fosamilacetate (sc) 的 ED50 为 1.60-2.37 mg/kg，可保护小鼠免受金黄色葡萄球菌 N133 诱导的实验性全身感染[1]。在大鼠和猴子中，头孢洛林醋酸酯水合物（10 mg/kg；皮下注射）迅速离开血液并成功转化为 T-91825 [1]。

以枯草芽孢杆菌为试验菌，抗生素培养基2为扩散培养基，采用微生物法测定活性ceftaroline/头孢他林浓度 (低检出限，0.25 mg/升；日内及日内变动<10%)。［2］

Using the neutropenic lung infection model, 17 clinical S. aureus isolates (2 MSSA, 15 MRSA) are investigated. For a duration of 24 hours, groups of six mice are treated with Ceftaroline fosamil starting three hours after inoculation. Doses of ceftaroline fosamil are injected subcutaneously in increments of 0.2 mL. Normal saline is given to control animals in the same amounts, ways, and intervals as the treatment plans[1].

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For ceftaroline, blood samples were taken from six healthy rabbits after administration of a ceftaroline acetate bolus of 10 and 30 mg/kg of body weight in order to determine the spontaneous drug kinetics. The simulation was intended to provide apparent values of pharmacokinetic parameters close to those observed in healthy volunteers after a 1-h infusion of a 600-mg dose (ca. 10 mg/kg) of ceftaroline acetate: mean half-life (t1/2), 1.57 to 2.63 h; peak concentration (Cmax), 18.96 to 21.02 mg/liter; and area under the curve (AUC), 56.08 mg·h/liter. A total dose of 58 mg/kg needed to be infused into the rabbit over a 12-h period in order to simulate the kinetics in human serum after the administration of a 10-mg/kg dose (i.e., 600 mg twice daily).
For each MRSA strain, the animals were randomly assigned to either no treatment (controls), ceftaroline regimen mimicking the human dose of 10 mg/kg every 12 h (q12h) (600 mg q12h), a linezolid regimen mimicking the human dose of 10 mg/kg q12h (600 mg q12h), and vancomycin administered by a constant intravenous infusion in order to reach a steady-state 20× MIC in serum.
Experimental endocarditis was induced with an inoculum of 108 CFU of S. aureus. Treatment was started 24 h after inoculation for a 4-day regimen. Aortic valve vegetations were excised, weighed, and then homogenized in 0.5 ml of saline buffer and used for quantitative cultures on agar for 24 h at 37°C. Dilutions at 10−1, 10−2, and 10−4 were prepared to eliminate potential carryover effects. To evaluate whether ceftaroline treatment could induce the selection of variants resistant in vivo, undiluted vegetation homogenates were spread on agar plates containing the active form of ceftaroline at a concentration corresponding to fourfold the MIC. Bacterial counts were determined after 48 h of incubation at 37°C.[2]

Absorption, Distribution and Excretion
primarily eliminated by the kidneys (6% in feces within 48 hours).
Median 20.3 L (18.3-21.6 L).

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Metabolism / Metabolites
Ceftaroline fosamil is converted into bioactive ceftaroline in plasma by a phosphatase enzyme. Hydrolysis of the beta-lactam ring of ceftaroline occurs to form the microbiologically inactive, open-ring metabolite ceftaroline M-1.

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Biological Half-Life
1.60 hours (600 mg dose).

Protein Binding
approximately 20%.

[1]. TAK-599, a novel N-phosphono type prodrug of anti-MRSA cephalosporin T-91825: synthesis, physicochemical and pharmacological properties. Bioorg Med Chem. 2003 May 29;11(11):2427-37.

[2]. Ceftaroline fosamil: a novel broad-spectrum cephalosporin with expanded anti-Gram-positive activity. J Antimicrob Chemother. 2010 Nov;65 Suppl 4:iv9-16.

[3]. Ceftaroline fosamil, a cephalosporin derivative for the potential treatment of MRSA infection. Curr Opin Investig Drugs. 2008 Feb;9(2):201-9.

Pharmacodynamics
The time that unbound plasma concentration of ceftaroline exceeds the minimum inhibitory concentration (MIC) of the infecting organism has been shown to best correlate with efficacy in a neutropenic murine thigh infection model with S. aureus and S. pneumoniae. No significant effect on QTc (corrected QT interval) interval was detected at peak plasma concentration or at any other time.

C22H22N8O8PS4+.C2H3O2-.H2O

762.752

762.041

400827-55-6

Ceftaroline fosamil;400827-46-5; 229016-73-3; 400827-55-6

16007393

Typically exists as solid at room temperature

1.884

393.38

6

20

10

48

1240

2

O.C([O-])(=O)C.C(C1=C(SC2=NC(C3=CC=[N+](C)C=C3)=CS2)CS[C@H]2N1C(=O)[C@H]2NC(=O)/C(=N\OCC)/C1N=C(NP(O)(O)=O)SN=1)(O)=O

KRWPPVCZNGQQHZ-IINIBMQSSA-N

InChI=1S/C22H21N8O8PS4.C2H4O2.H2O/c1-3-38-26-13(16-25-21(43-28-16)27-39(35,36)37)17(31)24-14-18(32)30-15(20(33)34)12(9-40-19(14)30)42-22-23-11(8-41-22)10-4-6-29(2)7-5-10;1-2(3)4;/h4-8,14,19H,3,9H2,1-2H3,(H4-,24,25,27,28,31,33,34,35,36,37);1H3,(H,3,4);1H2/b26-13-;;/t14-,19-;;/m1../s1

acetic acid;(6R,7R)-7-[[(2Z)-2-ethoxyimino-2-[5-(phosphonoamino)-1,2,4-thiadiazol-3-yl]acetyl]amino]-3-[[4-(1-methylpyridin-1-ium-4-yl)-1,3-thiazol-2-yl]sulfanyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate;hydrate

Ceftaroline fosamil hydrate; TAK-599 hydrate; TAK599 hydrate; PPI0903 hydrate; PPI-0903 hydrate

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)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

注意: 如下所列的是一些常用的体内动物实验溶解配方，主要用于溶解难溶或不溶于水的产品（水溶度<1 mg/mL）。 建议您先取少量样品进行尝试，如该配方可行，再根据实验需求增加样品量。

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注射用配方1: DMSO : Tween 80： Saline = 10 : 5 : 85 (如： 100 μL DMSO → 50 μL Tween 80 → 850 μL Saline)
*生理盐水/Saline的制备：将0.9g氯化钠/NaCl溶解在100 mL ddH ₂ O中，得到澄清溶液。
注射用配方 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL DMSO → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)
注射用配方 3: DMSO : Corn oil = 10 : 90 (如： 100 μL DMSO → 900 μL Corn oil)
示例: 以注射用配方 3 (DMSO : Corn oil = 10 : 90) 为例说明, 如果要配制 1 mL 2.5 mg/mL的工作液, 您可以取 100 μL 25 mg/mL 澄清的 DMSO 储备液，加到 900 μL Corn oil/玉米油中, 混合均匀。

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注射用配方 4: DMSO : 20% SBE-β-CD in Saline = 10 : 90 [如：100 μL DMSO → 900 μL (20% SBE-β-CD in Saline)]
*20% SBE-β-CD in Saline的制备（4°C，储存1周）：将2g SBE-β-CD (磺丁基-β-环糊精) 溶解于10mL生理盐水中，得到澄清溶液。
注射用配方 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (如： 500 μL 2-Hydroxypropyl-β-cyclodextrin (羟丙基环胡精)→ 500 μL Saline)
注射用配方 6: DMSO : PEG300 : Castor oil : Saline = 5 : 10 : 20 : 65 (如： 50 μL DMSO → 100 μL PEG300 → 200 μL Castor oil → 650 μL Saline)
注射用配方 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (如： 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
注射用配方 8: 溶解于Cremophor/Ethanol (50 : 50), 然后用生理盐水稀释。
注射用配方 9: EtOH : Corn oil = 10 : 90 (如： 100 μL EtOH → 900 μL Corn oil)
注射用配方 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL EtOH → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)

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口服配方 1: 悬浮于0.5% CMC Na (羧甲基纤维素钠)
口服配方 2: 悬浮于0.5% Carboxymethyl cellulose (羧甲基纤维素)
示例: 以口服配方 1 (悬浮于 0.5% CMC Na)为例说明, 如果要配制 100 mL 2.5 mg/mL 的工作液, 您可以先取0.5g CMC Na并将其溶解于100mL ddH2O中，得到0.5%CMC-Na澄清溶液；然后将250 mg待测化合物加到100 mL前述 0.5%CMC Na溶液中，得到悬浮液。

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口服配方 3: 溶解于 PEG400 (聚乙二醇400)
口服配方 4: 悬浮于0.2% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 5: 溶解于0.25% Tween 80 and 0.5% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 6: 做成粉末与食物混合

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注意: 以上为较为常见方法，仅供参考， InvivoChem并未独立验证这些配方的准确性。具体溶剂的选择首先应参照文献已报道溶解方法、配方或剂型，对于某些尚未有文献报道溶解方法的化合物，需通过前期实验来确定（建议先取少量样品进行尝试），包括产品的溶解情况、梯度设置、动物的耐受性等。

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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。