Endogenous Metabolite

目前正在研究5-氨基乙酰丙酸盐酸盐（ALA）（一种非荧光前药）是否能刺激恶性胶质瘤细胞中荧光卟啉的形成，从而用于术中肿瘤识别和切除。中位随访期为 35.4 个月（95% CI 1.0-56.7）。在接受 5-氨基乙酰丙酸治疗的 139 名患者中，有 90 名 (65%) 的所有对比增强肿瘤都被完全切除，而在接受白光治疗的 131 名患者中，只有 36 名 (36%) 出现了这种结果（组间差异为 29% [95% CI 17-40]，p < 0.0001）。接受 5-氨基乙酰丙酸治疗的患者的 6 个月无进展生存期高于接受白光治疗的患者（41.0% [32.8-49.2] vs 21.1% [14.0-28.2]；组间差异 19.9% [9.1] -30.7]，p= 0.0003，Z 检验）[1]。已经证明，5-ALA 本身不足以提供完全切除，且不会带来术后神经功能衰退的风险。此外，对于功能性 III 级神经胶质瘤，iMRI 与功能性神经导航相结合明显优于 5-ALA 切除方法 [2]。

尽管关于恶性胶质瘤细胞减灭术的争论仍在继续，但人们普遍认为，肿瘤减灭程度的增加可以提高总体生存率。然而，由于术中难以区分正常组织和病理组织，肿瘤切除范围的最大化受到阻碍。在此背景下，我们研究了两种已确立的肿瘤可视化方法，即5-ALA荧光引导手术和集成功能神经导航的术中MRI（iMRI），作为双术中可视化（DIV）方法。根据放射学表现，37名患者可能患有恶性胶质瘤（世界卫生组织III级或IV级）。iMRI确认了21个根据5-ALA技术显示完全切除的实验序列。iMRI无法确认14个根据5-ALA技术显示完整切除的序列，因为iMRI检测到了残留肿瘤。进一步的分析表明，这些序列可被归类为功能性II级肿瘤（邻近功能性脑区）。荧光引导切除和高场MRI术中评估的结合显著增加了该亚组邻近功能区的恶性胶质瘤的肿瘤切除范围，从61.7%增加到100%；仅5-ALA被证明不足以实现完全切除，而不会导致术后神经功能恶化的危险。此外，对于功能性III级胶质瘤，iMRI结合功能性神经导航明显优于5-ALA切除技术。切除范围可以从57.1%增加到71.2%，而不会导致术后神经功能缺损[2]。

检测97例ESCC患者病理标本中GPX4和HMOX1的表达，并进行预后分析。实时聚合酶链式反应（RT-PCR）、RNA微阵列和蛋白质印迹分析用于评估5-ALA在体外铁下垂中的作用。Ann Surg Oncol. 2021 Jul;28(7):3996-4006. https://pubmed.ncbi.nlm.nih.gov/33210267/

Dual Intraoperative Visualization (DIV) protocol[2]
Tumor volumetry was performed immediately prior to surgery. Tumor resection was then performed using the 5-ALA signal alone with the absence of a visible signal defining completeness of resection. This determination was carried out by the primary surgeon at all times. Functional neuronavigation data was intermittently projected to prevent inadvertent damage to functional brain areas. At the end of each stage of resection, the tumor cavity was systematically inspected to exclude residual tumor. Once the 5-ALA signal was undetectable, an iMRI scan was performed. If the extent of resection was confirmed, the decision to conclude the surgery was taken by the primary surgeon. Otherwise, the residual tumor volume was re-segmented and resection continued according to the neuronavigation. In all such cases the 5-ALA signal was redetected during further surgery once either the thin intervening layer of “healthy” brain parenchyma was removed and/or the viewing angle subsequently optimized. This procedure was repeated until the 5-ALA signal was no longer detectable, and the corresponding absence of contrast-enhancing tumor corroborated by iMRI. The additionally resected tissue detected by the iMRI was also analyzed by an experienced neuropathologist, confirming pathological glioma cell infiltration. In the event of persistence of 5-ALA in areas shown to be functional by the neuronavigation data, further surgery in the corresponding direction was intentionally terminated.

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In addition, this study used ferrostatin-1, a ferroptosis inhibitor, and a lipid peroxidation reagent against cell lines treated with 5-ALA. Finally, the role of 5-ALA was confirmed by its effect on an ESCC subcutaneous xenograft mouse model. Ann Surg Oncol. 2021 Jul;28(7):3996-4006. https://pubmed.ncbi.nlm.nih.gov/33210267/

Absorption
Oral bioavailability is 50-60%. ### **Topical gel** Pharmacokinetics (PK) of aminolevulinic acid (ALA) and PpIX was evaluated in a trial of 12 adult subjects with mild to moderate AK with at least 10 AK lesions on the face or forehead. A single dose of one entire tube of ALA (2 grams) was applied under occlusion for 3 hours followed by photodynamic therapy (PDT) to a total area of 20 cm2. The mean ± SD baseline plasma ALA and PpIX concentrations were 20.16 ± 16.53 ng/mL and 3.27 ± 2.40 ng/mL, respectively. In most subjects, an up to 2.5-fold increase of ALA plasma concentrations was observed during the first 3 hours after ALA application. The mean ± SD area under the concentration time curve (AUC0-t) and maximum concentration (Cmax) for baseline corrected ALA (n=12) were 142.83 ± 75.50 ng.h/mL and 27.19 ± 20.02 ng/mL, respectively. The median Tmax (time at which Cmax occurred) was 3 hours. ### **Topical solution** Two human pharmacokinetic (PK) studies were conducted in subjects with minimally to moderately thick actinic keratoses on the upper extremities, having at least 6 lesions on one upper extremity and at least 12 lesions on the other upper extremity. A single dose comprising of two topical applications of ALA topical solution (each containing 354 mg ALA HCl) were directly applied to the lesions and occluded for 3 hours prior to light treatment. The first PK study was conducted in 29 subjects and PK parameters of ALA were assessed. The baseline corrected mean ± SD of the maximum concentration (Cmax) of ALA was 249.9 ± 694.5 ng/mL and the median Tmax was 2 hours post dose. The mean ± SD exposure to ALA, as expressed by area under the concentration time curve (AUCt) was 669.9 ± 1610 ng·hr/mL. The mean ± SD elimination half-life (t1/2) of ALA was 5.7 ± 3.9 hours. A second PK study was conducted in 14 subjects and PK parameters of ALA and PpIX were measured. The baseline corrected PpIX concentrations were negative in at least 50% of samples in 50% (7/14) subjects and AUC could not be estimated reliably. The baseline-corrected mean ± SD of Cmax for ALA and PpIX was 95.6 ± 120.6 ng/mL and 0.95 ± 0.71 ng/mL, respectively. The median Tmax of ALA and PpIX was 2 hours post dose and 12 hours post dose, respectively. The mean AUCt of ALA was 261.1 ± 229.3 ng·hr/mL. The mean ± SD t1/2 of ALA was 8.5 ± 6.7 hours. ### **Oral solution** In 12 healthy subjects, the absolute bioavailability of ALA following the recommended dose of ALA solution was 100.0% + 1.1 with a range of 78.5% to 131.2%. Maximum ALA plasma concentrations were reached with a median of 0.8 hour (range 0.5 – 1.0 hour).

Route of Elimination
In 12 healthy subjects, excretion of parent aminolevulinic acid (ALA) in urine in the 12 hours following administration of the recommended dose of ALA solution was 34 + 8% (mean + std dev) with a range of 27% to 57%.

Volume of Distribution
In healthy volunteers, the administration of aminolevulinic acid resulted in a volume of distribution of 9.3 ± 2.8 L intravenously and 14.5 ± 2.5 orally.[11961050]

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Metabolism / Metabolites
Exogenous aminolevulinic acid (ALA) is metabolized to PpIX, but the fraction of administered ALA that is metabolized to PpIX is unknown. The average plasma AUC of PpIX is less than 6% of that of ALA.
Following topical administration, synthesis into protoporphyrin IX takes place in situ in the skin. Half Life: Mean half-life is 0.70 ± 0.18 h after the oral dose and 0.83 ± 0.05 h after the intravenous dose.

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Biological Half-Life
The mean ± SD elimination half-life (t1/2) of aminolevulinic acid was 5.7 ± 3.9 hours for the topical solution formulation and the mean half-life was 0.9 ± 1.2 hours for the oral solution formulation. In another pharmacokinetic studies with 6 healthy volunteers using a 128 mg dose, the mean half-life was 0.70 ± 0.18 h after the oral dose and 0.83 ± 0.05 h after the intravenous dose.

Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
No information is available on the use of oral aminolevulinic acid during breastfeeding. To minimize exposure of the infant, breastfeeding can be withheld for 24 hours after an oral dose. Breastfeeding is not expected to result in exposure of the child to topical aminolevulinic acid due to negligible systemic absorption. Aminolevulinic acid-induced photodynamic therapy has been used successfully to treat various skin lesions of the nipple. This treatment appeared to preserve nipple anatomy for breastfeeding.
◉ 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.

[1]. Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial. Lancet Oncol, 2006. 7(5): p. 392-401.

[2]. Improving the extent of malignant glioma resection by dual intraoperative visualization approach. PLoS One, 2012. 7(9): p. e44885.

5-aminolevulinic acid hydrochloride is a hydrochloride that is the monohydrochloride of 5-aminolevulinic acid. It is metabolised to protoporphyrin IX, a photoactive compound which accumulates in the skin. Used in combination with blue light illumination for the treatment of minimally to moderately thick actinic keratosis of the face or scalp. It has a role as an antineoplastic agent, a photosensitizing agent, a dermatologic drug and a prodrug. It contains a 5-ammoniolevulinic acid.
Aminolevulinic Acid Hydrochloride is the hydrochloride salt form of aminolevulinic acid, an aminoketone, used for local photosensitizing therapy. Aminolevulinic acid (ALA) is a metabolic pro-drug that is converted into the photosensitizer protoporphyrin IX (PpIX), which accumulates intracellularly. Upon exposure to light of appropriate wavelength (red, or blue), PpIX catalyzes oxygen to singlet oxygen, an intracellular toxin, which can further react to form superoxide and hydroxyl radicals. This leads to cellular cytotoxic effects.
A compound produced from succinyl-CoA and GLYCINE as an intermediate in heme synthesis. It is used as a PHOTOCHEMOTHERAPY for actinic KERATOSIS.
See also: Aminolevulinic Acid (has active moiety).

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Drug Indication
Gliolan is indicated in adult patients for visualisation of malignant tissue during surgery for malignant glioma (World Health Organization grade III and IV).
Treatment of actinic keratosis of mild to moderate severity on the face and scalp (Olsen grade 1 to 2; see section 5. 1) and of field cancer ization in adults. Treatment of superficial and/or nodular basal cell carcinoma unsuitable for surgical treatment due to possible treatment-related morbidity and/or poor cosmetic outcome in adults.

C5H10CLNO3

167.5908

167.034

C, 35.83; H, 6.01; Cl, 21.15; N, 8.36; O, 28.64

5451-09-2

5-Aminolevulinic acid-13C-1 hydrochloride;129720-94-1;5-Aminolevulinic acid-15N hydrochloride;116571-80-3;5-Aminolevulinic acid-d2 hydrochloride;187237-35-0;5-Aminolevulinic acid-13C hydrochloride;5-Aminolevulinic acid;106-60-5; 5451-09-2 (HCl); 106-60-5 (free); 868074-65-1 (phosphate)

123608

White to off-white solid powder

1.2±0.1 g/cm3

311.5±27.0 °C at 760 mmHg

~150 °C (dec.)

142.2±23.7 °C

0.0±1.4 mmHg at 25°C

1.482

-0.79

80.39

3

4

4

10

121

0

ZLHFONARZHCSET-UHFFFAOYSA-N

InChI=1S/C5H9NO3.ClH/c6-3-4(7)1-2-5(8)9;/h1-3,6H2,(H,8,9);1H

5-amino-4-oxopentanoic acid hydrochloride

5-ALA; ALA; dALA; 5-aminolevulinic acid; aminolevulinic acid; Aminolevulinic Acid HCl; Aminolevulinic acid hydrochloride; 5-Amino-4-oxopentanoic acid hydrochloride; Levulan Kerastick; delta-Aminolevulinic acid hydrochloride; Aminolevulinic Acid HCl; Aminolevulinic Acid hydrochloride; US trade name: Levulan.

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

注意： 请将本产品存放在密封且受保护的环境中，避免吸湿/受潮。

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

DMSO : ~100 mg/mL (~596.69 mM)
H2O : ~16.67 mg/mL (~99.47 mM)

配方 1 中的溶解度: ≥ 2.08 mg/mL (12.41 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 20.8 mg/mL澄清DMSO储备液加入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: ≥ 2.08 mg/mL (12.41 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in 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 20.8 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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配方 3 中的溶解度: ≥ 2.08 mg/mL (12.41 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 20.8 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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配方 4 中的溶解度: 100 mg/mL (596.69 mM) in PBS (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液; 超声助溶.

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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。