Carboxy finasteride   中文名称: 非那雄胺羧酸

Finasteride metabolite; 5α-reductase

本研究的目的是研究圣约翰草（SJW，贯叶连翘）治疗引起的诱导药物代谢对非那雄胺及其两种先前确定的I期代谢物（羟基非那雄胺和Carboxy finasteride/羧基非那雄胺）的血浆、胆道和尿液药代动力学的影响。12名健康男性在SJW （300mg b.i.d, hyperperforin 4%）治疗前后14天，通过多通道管道系统Loc-I-Gut的导管直接给予5mg非那雄胺。胆汁样本通过Loc-I-Gut装置从空肠近端取出。采用LC-ESI-MS/MS对血浆、胆汁和尿液中的非那雄胺及其代谢物进行分析。采用高效液相色谱-紫外分光光度法测定血浆中hyperperin的含量。中药处理显著降低了非那雄胺的血药浓度峰（C(max)）、血药-时间曲线下面积（AUC(0-24h)）和消除半衰期（t(1/2)）。几何平均比值（90% CI）分别为0.42（0.36 ~ 0.49）、0.66（0.56 ~ 0.79）和0.54（0.48 ~ 0.61）。非那雄胺少量排泄到胆汁和尿液中。血浆、胆汁和尿液中未检出羟基非那雄胺。羧基非那雄胺在所有三个室中定量，其血浆药代动力学受到SJW治疗的显著影响。在SJW治疗14天的最后一次给药后约12小时，血浆中hyperperin浓度为21+/-7ng/ml。综上所述，SJW治疗2周诱导了非那雄胺的代谢，并减少了该药物的血浆暴露。对药物及其代谢产物的胆尿排泄有了新的认识。［1］

The overall aim of this detailed investigation of the pharmacokinetics (PK) and metabolism of finasteride in pigs was to improve understanding of in vivo PK for this drug and its metabolites such as Carboxy finasteride. Specific aims were to examine the effects of ketoconazole coadministration on the PK in three plasma compartments (the portal, hepatic, and femoral veins), bile, and urine and to use these data to study in detail the intestinal absorption and the liver extraction ratio and apply a semiphysiological based PK model to the data. The pigs received an intrajejunal dose of finasteride (0.8 mg/kg) either alone (n = 5) or together with ketoconazole (10 mg/kg) (n = 5) or an intravenous dose (0.2 mg/kg) (n = 3). Plasma, bile, and urine (collected from 0 to 6 h) were analyzed with ultraperformance liquid chromatography-tandem mass spectrometry. Ketoconazole increased the bioavailability of finasteride from 0.36 ± 0.23 to 0.91 ± 0.1 (p < 0.05) and the terminal half-life from 1.6 ± 0.4 to 4.0 ± 1.1 h (p < 0.05). From deconvolution, it was found that the absorption rate from the intestine to the portal vein was rapid, and the product of the fraction absorbed and the fraction that escaped gut wall metabolism was high (f(a) · F(G) ∼ 1). Interestingly, the apparent absorption rate constant (k(a)) to the femoral vein was lower than that to the portal vein, probably because of binding and distribution within the liver. The liver extraction ratio was time-dependent and varied with the two routes of administration. After intrajejunal administration, from 1 to 6 h, the liver extraction ratio was significantly (p < 0.05) reduced by ketoconazole treatment from intermediate (0.41 ± 0.21) to low (0.21 ± 0.10).[2]
Reference: Drug Metab Dispos. 2011 May;39(5):847-57.

[1]. The effect of St. John’s wort on the pharmacokinetics, metabolism and biliary excretion of finasteride and its metabolites in healthy men. Eur J Pharm Sci. 2009 Mar 2;36(4-5):433-43.

[2]. In vivo investigation in pigs of intestinal absorption, hepatobiliary disposition, and metabolism of the 5α-reductase inhibitor finasteride and the effects of coadministered ketoconazole. Drug Metab Dispos . 2011 May;39(5):847-57.

Finasteride Carboxylic Acid is a 3-hydroxy steroid. It has a role as an androgen.

C23H34N2O4

402.53

402.252

116285-37-1

18632991

Typically exists as solid at room temperature

1.169g/cm3

658.3ºC at 760 mmHg

351.9ºC

4.94E-19mmHg at 25°C

1.542

3.598

95.5

3

4

3

29

775

7

C[C@]12CC[C@H]3[C@H]([C@@H]1CC[C@@H]2C(=O)NC(C)(C)C(=O)O)CC[C@@H]4[C@@]3(C=CC(=O)N4)C

OFTBMAPJHKDDJV-MKMSXTRJSA-N

InChI=1S/C23H34N2O4/c1-21(2,20(28)29)25-19(27)16-7-6-14-13-5-8-17-23(4,12-10-18(26)24-17)15(13)9-11-22(14,16)3/h10,12-17H,5-9,11H2,1-4H3,(H,24,26)(H,25,27)(H,28,29)/t13-,14-,15-,16+,17+,22-,23+/m0/s1

2-[[(1S,3aS,3bS,5aR,9aR,9bS,11aS)-9a,11a-dimethyl-7-oxo-1,2,3,3a,3b,4,5,5a,6,9b,10,11-dodecahydroindeno[5,4-f]quinoline-1-carbonyl]amino]-2-methylpropanoic acid

Finasteride Carboxylic Acid; 116285-37-1; Carboxy finasteride; UNII-K71S04GO1T; K71S04GO1T; 2-[[(1S,3aS,3bS,5aR,9aR,9bS,11aS)-9a,11a-dimethyl-7-oxo-1,2,3,3a,3b,4,5,5a,6,9b,10,11-dodecahydroindeno[5,4-f]quinoline-1-carbonyl]amino]-2-methylpropanoic acid; Alanine, 2-methyl-N-(((4aR,4bS,6aS,7S,9aS,9bS,11aR)-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-4a,6a-dimethyl-2-oxo-1H-indeno(5,4-f)quinolin-7-yl)carbonyl)-; Alanine, 2-methyl-N-[[(4aR,4bS,6aS,7S,9aS,9bS,11aR)-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-4a,6a-dimethyl-2-oxo-1H-indeno[5,4-f]quinolin-7-yl]carbonyl]-; Finasteride carboxylic acid

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！
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