Absorption, Distribution and Excretion
Corydalis saxicola Bunting (Yanhuanglian) is an important component in various prescriptions in traditional Chinese medicine. Yanhuanglian has been demonstrated to possess many pharmacological activities, including antibacterial, antiviral, and anticancer activities. The active fractions are dehydrocavidine, coptisine, dehydroapocavidine, and tetradehydroscoulerine. The purpose of the present study was to examine in vivo pharmacokinetics and tissue distribution in rats by using high-performance liquid chromatography (HPLC) coupled with tandem mass spectrometry. Systemic clearance of the four active alkaloids in plasma was over 93% of hepatic blood flow, indicating they may be quickly eliminated via hepatic clearance. Less than 10% drugs was excreted via urine following intravenous and oral administration, suggesting that these four alkaloids may undergo significant metabolism in the body or the drug may be excreted via other routes other than urine. There was significantly lower excretion of these four alkaloids following oral than intravenous administration, suggesting a significant first pass effect after oral administration. There appeared to be wide distribution of those four alkaloids in rats as demonstrated by the higher apparent volume of distribution. Our results have also demonstrated that the four alkaloids can be absorbed following oral administration although there were less than 15% of drugs absorbed into systemic circulation. In summary, the favorable oral bioavailability properties of those four active alkaloids in rats make Yanhuanglian extract worth further investigation for improving oral bioavailability.
To study the absorption of coptisine chloride (COP) and berberrubine (BRB) as chemical constituents of some traditional Chinese medicines in human intestinal epithelial. By using Caco-2 (the human colonic adenocarcinoma cell lines) cell monolayers as an intestinal epithelial cell model, the permeability of COP and BRB were studied from apical side (AP side) to basolateral side (BL side) or from BL side to AP side. The two alkaloids were measured by reversed-phase high performance liquid chromatography (HPLC) coupled with UV detector. Transport parameters and apparent permeability coefficients (P(app)) were then calculated and compared with those of propranolol and atenolol. P(app) values were also compared with the reported values for model compounds (propranolol and atenolol). The P(app) values of COP, BRB were (1.103 +/- 0.162) x 10(-5), (1.309 +/- 0.102) x 10(-5) cm x s(-1 from AP side to BL side, and (0.300 +/- 0.041) x 10(-5) and (1.955 +/- 0.055) x 10(-5) cm x s(-1) from BL side to AP side, respectively. Their P(app) values were identical with those of propranolol [(2.23 +/- 0.10) x 10(-5 cm x s(-1)], which is a transcellular transport marker and as a control substance for high permeability. On the other hand, the efflux transport of BRB was higher 1.49 times more than its influx transport with 0.67 rate of P(app A-->B)/P(app B-->A). But P(app A-->B)/P(app B-->A value of COP was 3.67, which suggested that the efflux transport have not been involved in its absorbed mechanism in Caco-2 cells monolayers. COP and BRB can be absorbed across intestinal epithelial cells, and they are completely absorbed compounds. BRB may have been involved in efflux mechanism in Caco-2 cells monolayers model from the basolateral-to-apical direction.
To determine the pharmacokinetics, distribution, and mutual transformation of the total alkaloids, jatrorrhizine, coptisine, berberine, and palmatine from Coptis chinensis in rats. After the total alkaloids and berberine were fed into rats, their contents in plasma, tissues and gastrointestinal tract were determined by reversed-phase HPLC. The peak times of berberine in blood were 2.0 hr (Cmax 3.7 mg x L(-1)) and 5.0 hr Cmax 2.8 mg x L(-1)), respectively. Berberine in rat blood can be transformed into jatrorrhizine. After the rats were fed with the total alkaloids by gavage, the content of berberine was decreased monotonously, while coptisine, palmatine, and jatrorrhizine contents were increased gradually in the stomach, it speculated that berberine may be transformed into jatrorrhizine in the stomach. Animal experiments showed that berberine and palmatine were mainly distributed in the lungs of animals, followed by the distribution in the liver, while jatrorrhizine and coptisine was mainly in the liver, then in the lungs. Berberine could transform into jatrorrhizine. The mechanism on the appearance of two maximum blood concentration of berberine in blood could be explained with the propulsion of the gastrointestinal tract partly.
The absorption and transport mechanisms of berberine, palmatine, jateorhizine, and coptisine were studied using a Caco-2 cells uptake and transport model, with the addition of cyclosporin A and verapamil as P-glycoprotein (P-gp) inhibitors and MK-571 as a multidrug resistance-associated protein 2 (MRP(2)) inhibitor. In the uptake experiment, berberine, palmatine, jateorhizine, and coptisine were all taken into Caco-2 cells, and their uptakes were increased in the presence of cyclosporin A or verapamil. In the transport experiment, P(app) (AP-BL) was between 0.1 and 1.0 x 10(6) cm/sec for berberine, palmatine, jateorhizine, and coptisine and was lower than P(app) (BL-AB). ER values were all >2. Cyclosporin A and verapamil both increased P(app) (AP-BL) but decreased P(app) (BL-AB) for berberine, palmatine, jateorhizine, and coptisine; ER values were decreased by >50%. MK-571 had no influence on the transmembrane transport of berberine, palmatine, jateorhizine, and coptisine. At a concentration of 1-100 uM, berberine, palmatine, jateorhizine, and coptisine had no significant effects on the bidirection transport of Rho123. Berberine, palmatine, jateorhizine, and coptisine were all P-gp substrates; and at the range of 1-100 uM, berberine, palmatine, jateorhizine, and coptisine had no inhibitory effects on P-gp.
Jiao-Tai-Wan (JTW), an important herbal formula consists of Rhizoma coptidis and Cortex cinnamomi powder, is a famous prescription which has been used for centuries to treat insomnia in Traditional Chinese Medicine. The purpose of this study is to compare the pharmacokinetic properties of five protoberberine-type alkaloids (i.e. berberine, palmatine, coptisine, epiberberine and jatrorrhizine), the main bioactive constituents in JTW, between normal and insomnic rats. We also investigate the differences between single-dose and multiple-dose pharmacokinetics of five protoberberine-type alkaloids. The insomnic rat models were induced by intraperitoneal injection of one-dose para-chlorophenylalanine acid (PCPA). Quantification of five protoberberine-type alkaloids in rat plasma was achieved by using a rapid LC-MS/MS method. Plasma samples were collected at different time points to construct pharmacokinetic profiles by plotting drug concentration versus time and estimate pharmacokinetic parameters. An unpaired Student's t test was used for comparisons with SPSS 17.0. The five protoberberine-type alkaloids of single-dose normal groups had slow absorption and low bioavailability, as well as a delay of peak time. In the single-dose oral administration, the Cmax and Tmax of five ingredients in insomnic rats had significant differences compared with those of normal rats. In the multiple-dose oral administration, the pharmacokinetic parameters of five protoberberine-type alkaloids varied greatly in insomnic rats. In the normal rats, there were significant differences (p<0.05) in the principal pharmacokinetic parameters such as Cmax and Tmax between single-dose and multiple-dose oral administration. In the insomnic rats, the five ingredients of multiple-dose groups showed better absorption than the single-dose groups. Particularly, three peaks were observed in multiple-dose model group of plasma-concentration curves. The pharmacokinetic behavior of five protoberberine-type alkaloids was described in this paper. In both normal groups and model groups, the pharmacokinetic behavior of multiple-dose had significant differences comparing with the single-dose; either single-dose or multiple-dose, the pharmacokinetic behavior of insomnic rats had significant differences comparing the normal rats. Multiple dosing may improve the absorption of JTW in insomnic rats, which will increase the bioavailability and bring into active role in therapeutical effect.

Toxicity Summary
IDENTIFICATION AND USE: Coptisine, a cytotoxic alkaloid found in Chinese goldthread, is related to berberine. It is used in biochemical studies and has been tested as experimental therapy. HUMAN EXPOSURE AND TOXICITY: Cytotoxicity evaluation of coptisine was conducted on a panel of human and murine cell lines in comparison with the established antitumor drugs mitoxantrone, doxorubicin (Dx), and cisplatin (CDDP). Coptisine was cytotoxic on LoVo and HT-29 and less potent on L-1210, and it was partially crossresistant on the human tumor colon cell line resistant to Dx, LoVo/Dx, whereas it was not significantly crossresistant on the murine leukemia cell line resistant to CDDP, L-1210/CDDP. Coptisine prevents vascular smooth muscle cell proliferation selectively at lower concentrations compared with various cells or other structurally related alkaloids. Coptisine has potential pharmacological activity for reducing cholesterol, and may reduce cholesterol by regulating mRNA and protein expressions of key genes involved in cholesterol metabolism, such as LDLR, CYP7A1, and HMGCR. ANIMAL STUDIES: Coptisine is a potent reversible inhibitor of type A monoamine oxidase. Coptisine inhibits proliferation of vascular smooth muscle cells. In the sub-chronic toxicity study, no mortality and morbidity were observed which could be related to coptisine treatment. Besides, there was no abnormality in clinical signs, body weights, organ weights, urinalysis, hematological parameters, gross necropsy, and histopathology in any of the animals after the oral administration of coptisine.

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Non-Human Toxicity Values
LD50 Mice oral 852.12 mg/kg

[1]. The IDO inhibitor coptisine ameliorates cognitive impairment in a mouse model of Alzheimer's disease. J Alzheimers Dis. 2015;43(1):291-302.

Coptisine is an alkaloid. It has a role as a metabolite.
Coptisine has been reported in Coptis omeiensis, Corydalis solida, and other organisms with data available.
See also: Sanguinaria canadensis root (part of); Chelidonium majus flowering top (part of).

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Therapeutic Uses
/EXPL THER/ Indoleamine 2,3-dioxygenase (IDO), the first and rate-limiting enzyme in the kynurenine pathway (KP) of tryptophan catabolism, was recently established as one of the potential players involved in the pathogenesis of Alzheimer's disease (AD). Coptisine is a main pharmacological active constituent of the traditional Chinese medicinal prescription Oren-gedoku-to (OGT) which has therapeutic potential for the treatment of AD. Our recent studies have demonstrated that OGT significantly inhibited recombinant human IDO activity, which shed light on the possible mechanism of OGT's action on AD. Here, we characterized the effects of coptisine in an AD mouse model on the basis of its IDO inhibitory ability. Coptisine was found to be an efficient uncompetitive IDO inhibitor with a Ki value of 5.8 uM and an IC50 value of 6.3 uM. In AbetaPP/PS1 transgenic mice, oral administration of coptisine inhibited IDO in the blood and decreased the activation of microglia and astrocytes, consequently prevented neuron loss, reduced amyloid plaque formation, and ameliorated impaired cognition. Neuronal pheochromocytoma (PC12) cells induced with amyloid-beta peptide 1-42 and interferon-gamma showed reduction of cell viability and enhancement of IDO activity, while coptisine treatment increased cell viability based on its reversal effect on the enhanced activity of IDO. In conclusion, our present findings provide further evidence supporting the critical links between IDO, KP, and AD, and demonstrate coptisine, a novel IDO inhibitor, as a potential new class of drugs for AD treatment.
/EXPL THER/ Excessive receptor activator of NF-kappaB ligand (RANKL) signaling causes enhanced osteoclast formation and bone resorption. The downregulation of RANKL expression and its downstream signals may be an effective therapeutic approach to the treatment of bone loss diseases such as osteoporosis. Here, we found that coptisine, one of the isoquinoline alkaloids from Coptidis Rhizoma, exhibited inhibitory effects on osteoclastogenesis in vitro. Although coptisine has been studied for its antipyretic, antiphotooxidative, dampness dispelling, antidote, antinociceptive, and anti-inflammatory activities in vitro and in vivo, its effects on osteoclastogenesis have not been investigated. Therefore, we evaluated the effects of coptisine on osteoblastic cells as well as osteoclast precursors for osteoclastogenesis in vitro. The addition of coptisine to cocultures of mouse bone marrow cells and primary osteoblastic cells with 10(-8) M 1alpha,25(OH)(2)D(3) caused significant inhibition of osteoclast formation in a dose-dependent manner. Reverse transcriptase polymerase chain reaction (RT-PCR) analyses revealed that coptisine inhibited RANKL gene expression and stimulated the osteoprotegerin gene expression induced by 1alpha,25(OH)(2)D(3) in osteoblastic cells. Coptisine strongly inhibited RANKL-induced osteoclast formation when added during the early stage of bone marrow macrophage (BMM) cultures, suggesting that it acts on osteoclast precursors to inhibit RANKL/RANK signaling. Among the RANK signaling pathways, coptisine inhibited NF-kappaB p65 phosphorylations, which are regulated in response to RANKL in BMMs. Coptisine also inhibited the RANKL-induced expression of NFATc1, which is a key transcription factor. In addition, 10 uM coptisine significantly inhibited both the survival of mature osteoclasts and their pit-forming activity in cocultures. Thus, coptisine has potential for the treatment or prevention of several bone diseases characterized by excessive bone destruction.
/EXPL THER/ Because myocardial infarction is a major cause of morbidity and mortality worldwide, protecting the heart from the ischemia is the focus of intense research. Coptisine is an isoquinoline alkaloid extracted form Coptidis Rhizoma. This study aims to elucidate if coptisine is responsible for cardioprotection using myocardial infarction (MI) rat models and investigate its potential mechanism of action. Myocardial infarction was produced in rats with 85 mg/kg isoproterenol administered subcutaneously twice at an interval of 24 hr. The rats were randomized into 7 groups: (I) Normal; (II) ISO; (III) ISO+fasudil; (IV) ISO+isosorbide dinitrate (ISDN), and (V-VII) ISO+coptisine (25, 50, and 100 mg/kg). Cardiac function and markers of cardiac ischemic were assessed after MI. Rats pretreated with coptisine (25, 50, and 100 mg/kg) for 21 days and received subcutaneously injected with ISO (85 mg/kg) on the 20th and 21st day at an interval of 24 hr. The results suggested that coptisine has strong antioxidant activity, and it can maintain cell membrane integrity, ameliorate mitochondrial respiratory dysfunction, reduce myocardial cells apoptosis, inhibit RhoA/ROCK expression induced by high-dose isoproterenol administration. Coptisine provided cardioprotection in a model of myocardial infarction, and therefore should be considered as a novel adjunctive therapy for attenuating myocardial damage.
/EXPL THER/ Uncontrolled cell proliferation and robust angiogenesis play critical roles in osteosarcoma growth and metastasis. In this study we explored novel agents derived from traditional Chinese medicinal herbs that potently inhibit osteosarcoma growth and metastasis. Coptisine, an active component of the herb Coptidis rhizoma, markedly inhibited aggressive osteosarcoma cell proliferation. Coptisine induced cell cycle arrest at the G0/G1 phase through downregulation of CDK4 and cyclin D1 expression and effectively suppressed tumor growth in a xenografted mouse model. Coptisine significantly impeded osteosarcoma cell migration, invasion, and capillary-like network formation by decreasing the expression of VE-cadherin and integrin beta3, and diminishing STAT3 phosphorylation. Coptisine significantly elevated blood erythrocyte and hemoglobin levels while still remaining within the normal range. It also moderately increased white blood cell and platelet counts. These data suggest that coptisine exerts a strong anti-osteosarcoma effect with very low toxicity and is a potential anti-osteosarcoma drug candidate.
/EXPL THER/ Coptis chinensis has been used for the treatment of inflammatory diseases in China and other Asian countries for centuries. However, the chemical constituents and mechanism underlying the anti-inflammatory activity of this medicinal plant are poorly understood. Here, coptisine, the main constituent of C. chinensis, was shown to potently inhibit the production of nitric oxide (NO) by suppressing the protein and mRNA expressions of inducible nitric oxide synthase (iNOS) in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. Coptisine also inhibited the production of the pro-inflammatory cytokines interleukin-1beta (IL-1beta) and interleukin-6 (IL-6) by suppressing expression of cytokine mRNA. Coptisine suppressed the degradation of inhibitor of nuclear factor kappaBalpha (IkappaBalpha) and phosphorylation of extracellular signal-regulated kinase (ERK), c-Jun NH2-terminal kinase (JNK), p38 mitogen-activated protein kinase (MAPK), and phosphoinositide 3-kinase/Akt (PI3K/Akt). Coptisine had no effect on the expression of toll-like receptor 4 (TLR-4) and myeloid differentiation factor 88 (MyD88) as well as LPS binding to TLR-4. Coptisine also inhibited carrageenan-elicited rat paw edema and reduced the release of TNF-alpha and NO in rat inflamed tissue. These results suggest that coptisine inhibits LPS-stimulated inflammation by blocking nuclear factor-kappa B, MAPK, and PI3K/Akt activation in macrophages, and can be used as an agent for the prevention and treatment of inflammatory diseases.

C38H28N2O12S

736.7001

417.051

1198398-71-8

Coptisine;3486-66-6

72322

Yellow to orange solid powder

3.5

40.8

0

4

0

24

502

0

XYHOBCMEDLZUMP-UHFFFAOYSA-N

InChI=1S/C19H14NO4/c1-2-16-19(24-10-21-16)14-8-20-4-3-12-6-17-18(23-9-22-17)7-13(12)15(20)5-11(1)14/h1-2,5-8H,3-4,9-10H2/q+1

5,7,17,19-tetraoxa-13-azoniahexacyclo[11.11.0.02,10.04,8.015,23.016,20]tetracosa-1(13),2,4(8),9,14,16(20),21,23-octaene

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 : ~1 mg/mL (~2.40 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));
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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；
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