LASMIDITAN (COL 144, LY 573144)   中文名称: 拉司米地坦

Absorption, Distribution and Excretion
Oral absorption of lasmiditan is quick, with a median tmax of 1.8 hours. An open-label study looking at absorption pharmacokinetics found the Cmax and AUC0-t of lasmiditan following oral administration to be 322.8 ± 122.0 ng/mL and 1892 ± 746.0 ng.h/mL, respectively. The oral bioavailability of lasmiditan has been reported as approximately 40%. Co-administration of lasmiditan with a high-fat meal increased its Cmax and AUC by 22% and 19%, respectively, and delayed Tmax by approximately 1 hour - these differences in absorption are relatively minor and unlikely to be clinically significant. Similarly, severe renal impairment and mild-moderate hepatic impairment were found to increase both AUC and Cmax, but not to a clinically significant extent.
Lasmiditan is eliminated primarily via metabolism, with renal excretion accounting for a small fraction of its total elimination. Of the small amount of drug found in the urine post-dose, approximately 66% is comprised of lasmiditan's S-M8 metabolite. Only 3% of an administered dose of lasmiditan was recovered unchanged in the urine, further implying a relatively extensive metabolism of this drug.
Lasmiditan has been shown to penetrate the blood-brain barrier.

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Metabolism / Metabolites
The hepatic and extra-hepatic metabolism of lasmiditan is catalyzed primarily by non-CYP enzymes, with ketone reduction appearing to be the primary pathway. While the specific enzymes involved in the metabolism of lasmiditan have not been elucidated, FDA labeling states that the following enzymes are _not_ involved in its metabolism: monoamine oxidases, CYP450 reductase, xanthine oxidase, alcohol dehydrogenase, aldehyde dehydrogenase, and aldo-keto reductases. The metabolites of lasmiditan have not been characterized in published research, but two of its metabolites (M7 and M18) are considered to be pharmacologically inactive.

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Biological Half-Life
The mean elimination half-life of lasmiditan is 5.7 hours.

Hepatotoxicity
In preregistration controlled trials of lasmiditan in several thousand patients, mild-to-moderate serum aminotransferase elevations arose in a small percentage of patients (1% or less) and overall rates were not different from those in placebo recipients. In the controlled trials and subsequently with general use, there have been no reports of liver injury with symptoms or jaundice attributed to lasmiditan.
Likelihood score: E (unlikely cause of clinically apparent acute liver injury).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
There is no published experience with lasmiditan during breastfeeding. If lasmiditan is required by the mother of an older infant, it is not a reason to discontinue breastfeeding, but until more data become available, an alternate drug may be preferred, especially while nursing a newborn or preterm infant.
◉ 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
Lasmiditan exhibits a concentration-independent plasma protein binding of approximately 55-60%.

[1]. Cephalalgia . 2010 Oct;30(10):1159-69.

[2]. J Headache Pain . 2012 Jun;13(4):271-5.

Pharmacodynamics
Lasmiditan belongs to a new and novel class of acute anti-migraine medications that exert their effects via inhibition of neuronal firing rather than vasoconstriction of cerebral arteries. Lasmiditan appears to have a relatively quick onset of action (an important characteristic in acute migraine treatment) with some patients reporting benefit within 20 minutes. Due to its ability to cause CNS depression (e.g. drowsiness, dizziness), lasmiditan may cause significant driving impairment and patients should be advised not to participate in activities requiring mental alertness for at least 8 hours after dosing. Lasmiditan may carry some potential for abuse and should be used with caution in patients who may be at risk of drug abuse - its controlled substance scheduling is currently under review in the United States by the Drug Enforcement Administration (DEA). The safety of lasmiditan in pregnancy is unknown and is currently being monitored with a pregnancy exposure registry created by Eli Lilly and Company.

C19H18F3N3O2

377.38

377.135

439239-90-4

11610526

Typically exists as solid at room temperature

1.4±0.1 g/cm3

433.3±45.0 °C at 760 mmHg

215.9±28.7 °C

0.0±1.0 mmHg at 25°C

1.585

1.9

62.3

1

7

4

27

530

0

FC1C([H])=C(C([H])=C(C=1C(N([H])C1=C([H])C([H])=C([H])C(C(C2([H])C([H])([H])C([H])([H])N(C([H])([H])[H])C([H])([H])C2([H])[H])=O)=N1)=O)F)F

XEDHVZKDSYZQBF-UHFFFAOYSA-N

InChI=1S/C19H18F3N3O2/c1-25-7-5-11(6-8-25)18(26)15-3-2-4-16(23-15)24-19(27)17-13(21)9-12(20)10-14(17)22/h2-4,9-11H,5-8H2,1H3,(H,23,24,27)

2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl]benzamide

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)

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。