在大鼠纹状体和人血小板中，valbenazine 表现出 VMAT2 结合亲和力，Kis 值分别为 110 和 150 nM [1]。

口服伐苯那嗪 (10 mg/kg) 会导致大鼠下垂，这主要是一种肾上腺素能反应，并会升高血浆催乳素，这主要是一种多巴胺能反应[1]。

Absorption, Distribution and Excretion
Valbenazine and its active metabolite ([+]-α-HTBZ) demonstrate approximate proportional increases for the area under the plasma concentration versus time curve (AUC) and maximum plasma concentration (Cmax) after single oral doses from 40 mg to 300 mg (i.e., 50% to 375% of the recommended treatment dose). Following oral administration, the time to reach maximum valbenazine plasma concentration (Tmax) ranges from 0.5 to 1.0 hours. Valbenazine reaches steady-state plasma concentrations within 1 week. The absolute oral bioavailability of valbenazine is approximately 49%. [+]-α-HTBZ gradually forms and reaches Cmax 4 to 8 hours after administration of valbenazine. Ingestion of a high-fat meal decreases valbenazine Cmax by approximately 47% and AUC by approximately 13%. [+]-α-HTBZ Cmax and AUC are unaffected.
Following the administration of a single 50-mg oral dose of radiolabeled C-valbenazine (i.e., ~63% of the recommended treatment dose), approximately 60% and 30% of the administered radioactivity was recovered in the urine and feces, respectively. Less than 2% was excreted as unchanged valbenazine or [+]-α-HTBZ in either urine or feces.
The mean steady-state volume of distribution of valbenazine is 92 L.
Valbenazine has a mean total plasma systemic clearance value of 7.2 L/hr.

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Metabolism / Metabolites
Valbenazine is extensively metabolized after oral administration by hydrolysis of the valine ester to form the active metabolite ([+]-α-HTBZ) and by oxidative metabolism, primarily by CYP3A4/5, to form mono-oxidized valbenazine and other minor metabolites. [+]-α-HTBZ appears to be further metabolized in part by CYP2D6.

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Biological Half-Life
Both Valbenazine and [+]-α-HTBZ have half-lives of 15 to 22 hours.

Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
No information is available on the use of valbenazine during breastfeeding in humans. Based on animal studies, the manufacturer recommends that breastfeeding be avoided during valbenazine therapy and for 5 days after the final dose.
◉ 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
The plasma protein binding of valbenazine and [+]-α-HTBZ is greater than 99% and approximately 64%, respectively.

[1]. Pharmacologic Characterization of Valbenazine (NBI-98854) and Its Metabolites. J Pharmacol Exp Ther. 2017 Jun;361(3):454-461.

Valbenazine is a modified metabolite of [tetrabenazine], and it is currently being approved for the treatment of various movement disorders, particularly tardive dyskinesia and chorea associated with Huntington's disease. Tardive dyskinesia has long been regarded as a consequence of anti-dopamine receptor therapy, and until 2008 with the advent of [tetrabenazine], most treatments were ineffective. However, challenges in using [tetrabenazine] as a treatment of tardive dyskinesia included frequent dosing and safety and tolerability concerns. On April 2017, valbenazine was approved by the FDA under the brand name INGREZZA as the first and only approved treatment for adults with Tardive Dyskinesia (TD). On August 2023, valbenazine was again approved by the FDA for the treatment of chorea associated with Huntington's disease respectively. This approval was supported by positive results in multiple trials, including the KINECT-HD Phase 3 study and the ongoing KINECT-HD2 open-label extension trial. The reduction in chorea severity was observed as early as 2 weeks after starting treatment with an initial dose of 40 mg.
Valbenazine is a Vesicular Monoamine Transporter 2 Inhibitor. The mechanism of action of valbenazine is as a Vesicular Monoamine Transporter 2 Inhibitor.
See also: Valbenazine tosylate (active moiety of).

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Drug Indication
Valbenazine is indicated for the treatment of adults with tardive dyskinesia and chorea associated with Huntington’s disease.
FDA Label

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Mechanism of Action
Although the exact mechanism of action of valbenzine is still unknown, it is thought be mediated through the reversible inhibition of vesicular monoamine transporter 2 (VMAT2), a transporter that regulates monoamine uptake from the cytoplasm to the synaptic vesicle for storage and release.

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Pharmacodynamics
Valbenazine inhibits human VMAT2 (Ki ~ 150 nM) with no appreciable binding affinity for VMAT1 (Ki > 10 µM). Valbenazine is converted to the active metabolite [+]-α-dihydrotetrabenazine ([+]-α-HTBZ). [+]-α-HTBZ also binds with relatively high affinity to human VMAT2 (Ki ~ 3 nM). Valbenazine and [+]-αHTBZ have no appreciable binding affinity (Ki > 5000 nM) for dopaminergic (including D2), serotonergic (including 5HT2B), adrenergic, histaminergic or muscarinic receptors, thus limiting off-target receptors binding for a more favorable safety profile. Valbenazine may cause an increase in the corrected QT interval in patients who are CYP2D6-poor metabolizers or who are taking a strong CYP2D6 or CYP3A4 inhibitor. An exposure-response analysis of clinical data from two healthy volunteer studies revealed increased QTc interval with higher plasma concentrations of the active metabolite. Based on this model, patients taking an valbenazine 60 mg or 80 mg dose with increased exposure to the metabolite (e.g., being a CYP2D6 poor metabolizer) may have a mean (upper bound of double-sided 90% CI) QT prolongation of 9.6 (12.0) msec or 11.7 (14.7) msec, respectively as compared to otherwise healthy volunteers given valbenazine, who had a respective mean (upper bound of double-sided 90% CI) QT prolongation of 5.3 (6.7) msec or 6.7 (8.4) msec.

C24H38N2O4

418.57

418.283

1025504-45-3

Valbenazine tosylate;1639208-54-0

24795069

Light yellow to yellow solid powder

1.1±0.1 g/cm3

507.2±50.0 °C at 760 mmHg

260.6±30.1 °C

0.0±1.3 mmHg at 25°C

1.548

4.31

74.02

1

6

8

30

569

4

CC(C)C[C@@H]1CN2CCC3=CC(=C(C=C3[C@H]2C[C@H]1OC(=O)[C@H](C(C)C)N)OC)OC

GEJDGVNQKABXKG-CFKGEZKQSA-N

InChI=1S/C24H38N2O4/c1-14(2)9-17-13-26-8-7-16-10-21(28-5)22(29-6)11-18(16)19(26)12-20(17)30-24(27)23(25)15(3)4/h10-11,14-15,17,19-20,23H,7-9,12-13,25H2,1-6H3/t17-,19-,20-,23+/m1/s1

[(2R,3R,11bR)-9,10-dimethoxy-3-(2-methylpropyl)-2,3,4,6,7,11b-hexahydro-1H-benzo[a]quinolizin-2-yl] (2S)-2-amino-3-methylbutanoate

Valbenazine; NBI-98854; MT-5199; NBI 98854; MT5199; NBI98854; MT 5199; trade name: Ingrezza

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 (5.97 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 (5.97 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。