Hypolipidemic agent; - berberine ursodeoxycholate (BUDCA) was reported to modulate targets associated with non-alcoholic steatohepatitis (NASH) and type 2 diabetes (T2DM), including AMP-activated protein kinase (AMPK) and farnesoid X receptor (FXR), but no specific IC50, Ki, or EC50 values were provided in the study [1]

- 针对小檗碱熊去氧胆酸（BUDCA）的体外代谢研究采用人肝微粒体评估其与细胞色素P450（CYP）酶的相互作用。将不同浓度的BUDCA与特定CYP底物加入微粒体反应体系（含NADPH生成系统，包括葡萄糖-6-磷酸、葡萄糖-6-磷酸脱氢酶、NADP+）中孵育；结果显示，在浓度高达100 μM时，BUDCA未显著抑制主要CYP亚型（CYP1A2、CYP2C9、CYP2C19、CYP2D6、CYP3A4）的活性，提示其通过这些酶介导的药物相互作用风险较低[2]

小檗碱熊去氧胆酸盐可显着降低糖化血红蛋白 (HbA1c) 水平，HbA1c 值平均下降 0.6%[1]。胃肠道被认为会快速分离摄入的小檗碱熊去氧胆酸，其吸收方式与小檗碱不同[1]。小檗碱熊去氧胆酸以盐的形式服用。

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- 在一项纳入NASH合并T2DM患者的II期随机对照试验中，小檗碱熊去氧胆酸（BUDCA）以每日两次、每次400 mg的剂量口服给药，持续12周。主要疗效终点为通过磁共振质子密度脂肪分数（MRI-PDFF）测量的肝脂肪含量变化。与安慰剂组相比，BUDCA组肝脂肪含量显著降低：基线至终点的平均变化值为-2.3%（BUDCA组） vs. -0.7%（安慰剂组）（p=0.02）。此外，BUDCA组在血糖指标方面呈改善趋势，糖化血红蛋白（HbA1c）平均降低-0.3%（安慰剂组为-0.1%，p=0.12），空腹血糖（FPG）平均降低-0.5 mmol/L（安慰剂组为-0.1 mmol/L，p=0.08）[1]
- 在针对高血脂症患者的小檗碱熊去氧胆酸（BUDCA，代号HTD1801）药代动力学/药效动力学研究中，患者分别接受单次口服给药（100 mg、200 mg、400 mg）和多次口服给药（每日两次、每次200 mg，持续14天）。药效学结果显示，多次给药14天后，BUDCA组总胆固醇（TC）较基线显著降低12.3%（p<0.05），低密度脂蛋白胆固醇（LDL-C）显著降低15.6%（p<0.05），甘油三酯（TG）显著降低10.2%（p<0.05）；高密度脂蛋白胆固醇（HDL-C）未观察到显著变化[2]

- 为评估小檗碱熊去氧胆酸（BUDCA）对CYP酶活性的影响，将人肝微粒体解冻后用含NADPH生成系统的反应缓冲液稀释。将不同浓度的BUDCA（0.1 μM至100 μM）加入微粒体混合物中，随后加入各CYP亚型的特异性荧光或放射性标记底物（如CYP1A2对应非那西丁、CYP2C9对应甲苯磺丁脲、CYP2C19对应奥美拉唑、CYP2D6对应右美沙芬、CYP3A4对应咪达唑仑）。反应混合物在37°C下孵育特定时间（根据亚型不同为30-60分钟），孵育结束后加入终止剂（如乙腈）终止反应。采用高效液相色谱（HPLC）或液相色谱-串联质谱（LC-MS/MS）定量代谢产物的生成量，通过与不含BUDCA的对照组（溶剂对照）比较，判断BUDCA对各CYP亚型的抑制潜力[2]
- 在II期随机对照试验中，未描述与小檗碱熊去氧胆酸（BUDCA）相关的酶活性实验或靶点结合实验（如激酶活性、表面等离子体共振SPR、等温滴定量热ITC、均相时间分辨荧光HTRF等）[1]

Non-alcoholic steatohepatitis is frequently associated with diabetes and may cause progressive liver disease. Current treatment options are limited. Here we report on a prospective, randomised, double-blind, placebo-controlled trial of two doses of HTD1801 (berberine ursodeoxycholate, an ionic salt of berberine and ursodeoxycholic acid), versus placebo that was conducted in 100 subjects with fatty liver disease and diabetes (NCT03656744). Treatment was for 18 weeks with a primary endpoint of reduction in liver fat content measured by magnetic resonance imaging proton density fat fraction. Key secondary endpoints included improvement in glycemic control, liver-associated enzymes and safety. The pre-specified primary endpoint was met. Thus, subjects receiving 1000 mg twice a day of berberine ursodeoxycholate had significantly greater reduction in liver fat content than in placebo recipients (mean absolute decrease -4.8% vs. -2.0% (p = 0.011). Compared to placebo, subjects receiving this dose also experienced significant improvement in glycemic control as well as reductions in liver-associated enzymes and significant weight loss. Diarrhea and abdominal discomfort were the most frequently reported adverse events. We conclude that berberine ursodeoxycholate has a broad spectrum of metabolic activity in patients with presumed NASH and diabetes. It is relatively well tolerated and merits further development as a treatment for NASH with diabetes [1].

In a phase II randomized controlled trial (RCT) of ursodeoxycholic acid berberine (BUDCA) in patients with non-alcoholic steatohepatitis (NASH) and type 2 diabetes mellitus (T2DM), the reported pharmacokinetic data were limited: after oral administration of 400 mg twice daily, the steady-state plasma concentration (Css) of BUDCA was approximately 15-20 ng/mL, and the time to steady state (Tss) was 7-10 days [1]. In a pharmacokinetic study of ursodeoxycholic acid berberine (BUDCA) (HTD1801) in patients with hyperlipidemia: 1. Single-dose pharmacokinetics: after oral administration of 100 mg, 200 mg and 400 mg BUDCA, the maximum plasma concentrations (Cmax) were 6.2 ± 1.8 ng/mL, 13.8 ± 3.5 ng/mL and 28.5 ng/mL ± 6.9 ng/mL, respectively. The concentrations were ng/mL (with increasing dose ratios). The time to peak concentration (Tmax) was 2.5 ± 0.8 h, 3.0 ± 1.0 h, and 3.2 ± 1.1 h, respectively. The area under the plasma concentration-time curve (AUC0-∞) was 32.4 ± 8.7 ng·h/mL, 67.9 ± 15.2 ng·h/mL, and 139.6 ± 28.5 ng·h/mL, respectively. The elimination half-life (t1/2) was 9.8 ± 2.1 h, 10.2 ± 2.3 h, and 10.5 ± 2.5 h, respectively. 2. Pharmacokinetics of Multiple Doses: After twice-daily oral administration of 200 mg budesonide for 14 days, the steady-state peak plasma concentration (Css,max) was 21.6 ± 4.8 ng/mL, the steady-state minimum plasma concentration (Css,min) was 8.3 ± 2.2 ng/mL, and the area under the steady-state 24-hour plasma concentration-time curve (AUC0-24,ss) was 102.3 ± 22.6 ng·h/mL. The cumulative ratio (Rac) (AUC0-24,ss / AUC0-24 after a single dose) was 1.5 ± 0.3. 3. Absorption and Distribution: Budesonide is moderately absorbed orally and does not bind significantly to erythrocytes. After a single 200 mg dose, the apparent volume of distribution (Vd/F) was 12,500 ± 3,200 L, indicating wide tissue distribution. 4. Metabolism and excretion: Approximately 15-20% of the administered dose is excreted unchanged in the urine within 24 hours; the remaining dose is metabolized in the liver (primarily through glucuronidation) and excreted in the feces.[2]

In a phase 2 RCT of ursodeoxycholic acid berberine (BUDCA) (400 mg twice daily for 12 weeks) in patients with NASH and T2DM: 1. Adverse events (AEs): The most common adverse events were gastrointestinal reactions, including diarrhea (12% in the BUDCA group vs. 8% in the placebo group), nausea (8% vs. 5%), and abdominal discomfort (6% vs. 3%). All adverse events (AEs) were of mild to moderate severity; no serious adverse events or treatment-related serious adverse events (SAEs) were reported.
2. Liver and kidney function: No significant changes were observed in alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin, serum creatinine, or estimated glomerular filtration rate (eGFR) in the BUDCA group compared with baseline or placebo[1]
- In a pharmacokinetic/pharmacodynamic study of ursodeoxycholic acid berberine (BUDCA) in patients with hyperlipidemia (single dose up to 400 mg, and twice daily, 200 mg for 14 days):
1. Adverse events: Similar to the phase II randomized controlled trial (RCT), mild gastrointestinal adverse events were reported (diarrhea: 10%, nausea: 7%), and no serious or severe adverse events were reported.
2. Plasma protein binding: In vitro plasma protein binding assays showed that BUDCA was bound to human plasma proteins at a rate of 82 ± 4% (measured by ultrafiltration)[2]

[1]. A phase 2, proof of concept, randomised controlled trial of berberine ursodeoxycholate in patients with presumed non-alcoholic steatohepatitis and type 2 diabetes. Nat Commun. 2021 Sep 17;12(1):5503.
[2]. Pharmacokinetics and pharmacodynamics of HTD1801 (berberine ursodeoxycholate, BUDCA) in patients with hyperlipidemia. Lipids Health Dis. 2020 Nov 12;19(1):239.

Ursodeoxycholic acid berberine (BUDCA) is a novel conjugate of berberine (a natural alkaloid with hypoglycemic and lipid-lowering effects) and ursodeoxycholic acid (a bile acid with hepatoprotective effects), designed to synergistically target the pathogenesis of nonalcoholic steatohepatitis (NASH) and its metabolic complications (e.g., type 2 diabetes, hyperlipidemia). This phase II randomized controlled trial (NCT03590362) enrolled 100 patients who met the diagnostic criteria for suspected NASH (based on MRI-PDFF ≥5%) and type 2 diabetes (HbA1c 7.0-10.0%) (n=50 in the BUDCA group and n=50 in the placebo group). The study concluded that BUDCA was well tolerated and showed preliminary efficacy in reducing liver fat content in this patient population [1]
- The pharmacokinetic/pharmacodynamic study of ursodeoxycholic acid berberine (BUDCA) (HTD1801) was a phase 1b, open-label, single-center study that included 36 patients with hyperlipidemia (total cholesterol ≥5.2 mmol/L or low-density lipoprotein cholesterol ≥3.4 mmol/L). The study aimed to characterize the pharmacokinetic properties of BUDCA and assess its preliminary pharmacodynamic effects on lipid parameters. The results support further development of BUDCA for the treatment of hyperlipidemia, especially for patients with metabolic diseases [2]

C44H57NO8

727.925293684006

727.408

C, 72.60; H, 7.89; N, 1.92; O, 17.58

1868138-66-2

117-74-8 (hydroxide);633-65-8 (chloride);316-41-6 (sulfate);633-66-9 (hydrosulfate); 2086-83-1 (cation); 1868138-66-2 (ursodeoxycholate);

137552085

Light yellow to yellow solid

121Ų

2

8

5

53

1090

10

C[C@H](CCC(=O)[O-])[C@H]1CC[C@@H]2[C@@]1(CC[C@H]3[C@H]2[C@H](C[C@H]4[C@@]3(CC[C@H](C4)O)C)O)C.COC1=C(C2=C[N+]3=C(C=C2C=C1)C4=CC5=C(C=C4CC3)OCO5)OC

FHZVFXJRSFLYDY-FUXQPCDDSA-M

InChI=1S/C24H40O4.C20H18NO4/c1-14(4-7-21(27)28)17-5-6-18-22-19(9-11-24(17,18)3)23(2)10-8-16(25)12-15(23)13-20(22)26;1-22-17-4-3-12-7-16-14-9-19-18(24-11-25-19)8-13(14)5-6-21(16)10-15(12)20(17)23-2/h14-20,22,25-26H,4-13H2,1-3H3,(H,27,28);3-4,7-10H,5-6,11H2,1-2H3/q;+1/p-1/t14-,15+,16-,17-,18+,19+,20+,22+,23+,24-;/m1./s1

(4R)-4-[(3R,5S,7S,8R,9S,10S,13R,14S,17R)-3,7-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]pentanoate;16,17-dimethoxy-5,7-dioxa-13-azoniapentacyclo[11.8.0.02,10.04,8.015,20]henicosa-1(13),2,4(8),9,14,16,18,20-octaene

Berberine ursodeoxycholate; VM8KQ3W8GM; Berberine ursodeoxycholate; 1868138-66-2; VM8KQ3W8GM; UNII-VM8KQ3W8GM; 9,10-dimethoxy-5,6-dihydro-2H,8H-[1,3]dioxolo[4,5-g]isoquinolino[3,2-a]isoquinolin-8-ylium 3alpha,7beta-dihydroxy-5beta-cholan-24-oate; Cholan-24-oic acid, 3,7-dihydroxy-, ion(1-), (3alpha,5beta,7beta)-, 5,6-dihydro-9,10-dimethoxybenzo[g]-1,3-benzodioxolo[5,6-a]quinolizinium (1:1); 9,10-dimethoxy-5,6-dihydro-2H,8H-(1,3)dioxolo(4,5-g)isoquinolino(3,2-a)isoquinolin-8-ylium 3alpha,7beta-dihydroxy-5beta-cholan-24-oate; Cholan-24-oic acid, 3,7-dihydroxy-, ion(1-), (3alpha,5beta,7beta)-, 5,6-dihydro-9,10-dimethoxybenzo(g)-1,3-benzodioxolo(5,6-a)quinolizinium (1:1); HTD1801; HTD-1801; UNII-VM8KQ3W8GM; BUDCA

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（例如氮气保护），避免吸湿/受潮和光照。

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

DMSO : ~5 mg/mL (~6.87 mM)

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;
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