(5S,7S,8R)-4-hydroxy-8-methyl-3,5,7-tris(3-methylbut-2-enyl)-8-(4-methylpent-3-enyl)-1-(2-methylpropanoyl)bicyclo[3.3.1]non-3-ene-2,9-dione

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 异戊烯醇脂质
• 英文名称: (5S,7S,8R)-4-hydroxy-8-methyl-3,5,7-tris(3-methylbut-2-enyl)-8-(4-methylpent-3-enyl)-1-(2-methylpropanoyl)bicyclo[3.3.1]non-3-ene-2,9-dione
• 化学式: C₃₅H₅₂O₄
• 分子量: 536.8
• InChiKey: KGSZHKRKHXOAMG-COGANRFPSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  9.6
• 重原子数：
  39
• 可旋转键数：
  11
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.63
• 拓扑面积：
  71.4
• 氢给体数：
  1
• 氢受体数：
  4

ADMET

代谢

贯叶连翘素是圣约翰草（贯叶连翘）中的一个重要活性成分，被认为可能是圣约翰草抗抑郁效果和草药-药物相互作用的原因。在这项研究中，使用来自雄性和雌性Sprague-Dawley大鼠的肝微体，以及在苯巴比妥或地塞米松诱导或不诱导的情况下，研究了贯叶连翘素的体外代谢谱。通过高效液相色谱法分离并鉴定了四种主要的I相代谢物，分别命名为19-羟基贯叶连翘素、24-羟基贯叶连翘素、29-羟基贯叶连翘素和34-羟基贯叶连翘素，并通过质谱和核磁共振进行了鉴定。结果表明，羟基化是大鼠肝脏中贯叶连翘素途径的主要生物转化，可诱导的细胞色素P450 3A（CYP450 3A）和/或CYP2B可能是催化这些羟基化反应的主要细胞色素P450同种物。

Hyperforin is an important active component of St. John's wort (Hypericum perforatum) that has been suggested to be responsible for the St. John's wort antidepressive effects and herbal-drug interactions. In this study, the in vitro metabolism profile of hyperforin was investigated using liver microsomes from male and female Sprague-Dawley rats, with or without induction by phenobarbital or dexamethasone. Four major Phase I metabolites, named 19-hydroxyhyperforin, 24-hydroxyhyperforin, 29-hydroxyhyperforin, and 34-hydroxyhyperforin, were isolated by high performance liquid chromatography and identified by mass spectrometry and NMR. Results suggest that hydroxylation is a major biotransformation of the hyperforin pathway in rat liver and that inducible cytochrome P450 3A (CYP450 3A) and/or CYP2B may be the major cytochrome P450 isoforms catalyzing these hydroxylation reactions.

来源:Hazardous Substances Data Bank (HSDB)

代谢

对贯叶连翘的地上部分进行反复检查，得到了一种新的贯叶金丝桃素（1）的降解产物，即去氧呋喃贯叶金丝桃素A（2），以及之前已知的呋喃贯叶金丝桃素（3）、呋喃阿多贯叶金丝桃素（4）、呋喃贯叶金丝桃素A（5a和5b）、吡喃[7,28-b]贯叶金丝桃素（6）和3-甲基-4,6-二(3-甲基-2-丁烯基)-2-(2-甲基-1-氧代丙基)-3-(4-甲基-3-戊烯基)-环己酮（7）。

Repeated examination of the aerial parts of Hypericum perforatum yielded a new degradation product of hyperforin (1) namely deoxyfurohyperforin A (2), together with the previously identified furohyperforin (3), furoadhyperforin (4), furohyperforin A (5a and 5b), pyrano[7,28-b]hyperforin (6) and 3-methyl-4,6-di(3-methyl-2-butenyl)-2-(2-methyl-1-oxopropyl)-3-(4-methyl-3-pentenyl)-cyclohexanone (7).

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

与SJW（贯叶连翘，一种草药）联合用药导致血浆中多种药物浓度降低，包括阿米替林、环孢素、地高辛、印地那韦、伊立替康、华法林、苯丙香豆素、阿普唑仑、右美沙芬、辛伐他汀以及口服避孕药。

Co-medication with SJW resulted in decreased plasma concentrations of a number of drugs including amitriptyline, cyclosporine, digoxin, indinavir, irinotecan, warfarin, phenprocoumon, alprazolam, dextrometorphane, simvastatin, and oral contraceptives.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

/SRP:/ 立即急救：确保已经进行了充分的中和。如果患者停止呼吸，请开始人工呼吸，最好使用需求阀复苏器、球囊阀面罩设备或口袋面罩，按训练操作。如有必要，执行心肺复苏。立即用缓慢流动的水冲洗受污染的眼睛。不要催吐。如果患者呕吐，让患者向前倾或将其置于左侧（如果可能的话，头部向下），以保持呼吸道畅通，防止吸入。保持患者安静，维持正常体温。寻求医疗帮助。 /毒物A和B/

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

/SRP:/ 基本治疗：建立专利气道（如有需要，使用口咽或鼻咽气道）。如有必要，进行吸痰。观察呼吸不足的迹象，如有需要，辅助通气。通过非循环呼吸面罩以10至15升/分钟的速度给予氧气。监测肺水肿，如有必要，进行治疗……。监测休克，如有必要，进行治疗……。预防癫痫发作，如有必要，进行治疗……。对于眼睛污染，立即用水冲洗眼睛。在运输过程中，用0.9%的生理盐水（NS）持续冲洗每只眼睛……。不要使用催吐剂。对于摄入，如果患者能吞咽、有强烈的干呕反射且不流口水，则用温水冲洗口腔，并给予5毫升/千克，最多200毫升的水进行稀释……。在去污后，用干燥的无菌敷料覆盖皮肤烧伤……。/毒药A和B/

/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

/SRP:/ 高级治疗：对于无意识、严重肺水肿或严重呼吸困难的病人，考虑进行口咽或鼻咽气管插管以控制气道。使用气囊面罩装置的正压通气技术可能有益。考虑使用药物治疗肺水肿……。对于严重的支气管痉挛，考虑给予β激动剂，如沙丁胺醇……。监测心率和必要时治疗心律失常……。开始静脉输注D5W /SRP: "保持开放"，最低流量/。如果出现低血容量的迹象，使用0.9%生理盐水（NS）或乳酸林格氏液。对于伴有低血容量迹象的低血压，谨慎给予液体。注意液体过载的迹象……。使用地西泮或劳拉西泮治疗癫痫……。使用丙美卡因氢氯化物协助眼部冲洗……。 /Poisons A and B/

/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 人类毒性摘录

/其他毒性信息/ 最近，中草药与合成药物之间的相互作用引起了特别的关注。在过去的3年里，有超过50篇论文发表了关于圣约翰草（金丝桃Hypericum perforatum L.；SJW）与处方药之间相互作用的研究。与SJW联合用药导致了一些药物的血药浓度降低，包括阿米替林、环孢素、地高辛、印地那韦、伊立替康、华法林、苯丙香豆素、阿普唑仑、右美沙芬、辛伐他汀和口服避孕药。相互作用研究和病例报告的充分证据表明，SJW是细胞色素P450酶（尤其是CYP3A4）和/或P-糖蛋白的强诱导剂。最近的研究表明，SJW诱导酶的程度与产品中含有的金丝桃素量密切相关。不含大量金丝桃素（<1%）的产品并未显示出临床上相关的酶诱导作用。另一方面，一些证据表明金丝桃素也可能有助于SJW的抗抑郁活性。然而，使用低金丝桃素量（<1%）的SJW制剂的临床研究表明，这种植物提取物在治疗轻中度抑郁方面明显优于安慰剂，并且与丙米嗪和氟西汀相当。在本文中，对临床上显著的SJW相互作用进行了批判性的评估，特别是考虑到金丝桃素的影响。

/OTHER TOXICITY INFORMATION/ Recently, interactions of herbal medicines with synthetic drugs came into focus of particular interest. In the past 3 years, more than 50 papers were published regarding interactions between St. John's wort (Hypericum perforatum L.; SJW) and prescription drugs. Co-medication with SJW resulted in decreased plasma concentrations of a number of drugs including amitriptyline, cyclosporine, digoxin, indinavir, irinotecan, warfarin, phenprocoumon, alprazolam, dextrometorphane, simvastatin, and oral contraceptives. Sufficient evidence from interaction studies and case reports indicate that SJW is a potent inducer of cytochrome P450 enzymes (particularly CYP3A4) and/or P-glycoprotein. Recent studies could show that the degree of enzyme induction by SJW correlates strongly with the amount of hyperforin found in the product. Products that do not contain substantial amounts of hyperforin (<1%) have not been shown to produce clinically relevant enzyme induction. On the other hand, some evidence suggests that hyperforin may also contribute to the antidepressant activity of SJW. However, clinical studies using SJW preparations with a low hyperforin amount (<1%) clearly demonstrated the superiority of this plant extract over placebo and its equivalence to imipramine and fluoxetine in the treatment of mild to moderate forms of depression. In the present paper clinically significant SJW interactions are critically evaluated against the background of hyperforin.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

适合于测定服用含酒精度贯叶连翘提取物后血浆中贯叶连翘素的验证分析方法被描述。在大鼠口服300毫克/千克贯叶连翘提取物（WS 5572，含5%贯叶连翘素）后，通过HPLC和UV检测方法测定，大约3小时后达到大约370纳克/毫升（约690纳摩尔）的最大血浆水平。估计的半衰期和清除率分别为6小时和70毫升/分钟/千克。由于治疗剂量的贯叶连翘提取物远低于大鼠使用的剂量，因此开发了一种更灵敏的LC/MS/MS方法。该方法的定量下限为1纳克/毫升。使用此方法，可以在健康志愿者服用含300毫克贯叶连翘提取物（相当于14.8毫克贯叶连翘素）的薄膜包衣片后长达24小时内跟踪血浆中的贯叶连翘素水平。大约3.5小时后达到大约150纳克/毫升（约280纳摩尔）的最大血浆水平。半衰期和平均滞留时间分别为9小时和12小时。贯叶连翘素的药代动力学在600毫克提取物范围内呈线性。将剂量增加到900或1200毫克提取物时，Cmax和AUC值低于从低剂量数据的线性外推预期。志愿者体内的血浆浓度曲线很好地符合开放式两室模型。在重复剂量研究中，未观察到血浆中贯叶连翘素的积累。使用重复剂量研究的观察到的AUC值，估计在服用3 x 300毫克/日的提取物后，即正常治疗剂量方案后，贯叶连翘素的稳态血浆浓度大约为100纳克/毫升（约180纳摩尔）。

Validated analytical methods suitable for determining hyperforin in plasma after administration of alcoholic Hypericum perforatum extracts containing hyperforin are described. After oral administration of 300 mg/kg Hypericum extract (WS 5572, containing 5% hyperforin) to rats maximum plasma levels of approximately 370 ng/ml (approx. 690 nM) were reached after 3 hr, as quantified by a HPLC and UV detection method. Estimated half-life and clearance values were 6 hr and 70 ml/min/kg respectively. Since therapeutic doses of Hypericum extracts are much lower than that used in rats, a more sensitive LC/MS/MS method was developed. The lower limit of quantification of this method was 1 ng/ml. Using this method, plasma levels of hyperforin could be followed for up to 24 hr in healthy volunteers after administration of film coated tablets containing 300 mg hypericum extracts representing 14.8 mg hyperforin. The maximum plasma levels of approximately 150 ng/ml (approx. 280 nM) were reached 3.5 hr after administration. Half-life and mean residence time were 9 and 12 hr respectively. Hyperforin pharmacokinetics were linear up to 600 mg of the extract. Increasing the doses to 900 or 1200 mg of extract resulted in lower Cmax and AUC values than those expected from linear extrapolation of data from lower doses. Plasma concentration curves in volunteers fitted well in an open two-compartment model. In a repeated dose study, no accumulation of hyperforin in plasma was observed. Using the observed AUC values from the repeated dose study, the estimated steady state plasma concentrations of hyperforin after 3 x 300 mg/day of the extract, i.e., after normal therapeutic dose regimen, was approximately 100 ng/ml (approx. 180 nM).

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

在大鼠口服300 mg/kg的圣约翰草提取物（WS 5572，含5%金丝桃素）后，通过高效液相色谱和紫外检测方法测定，大约3小时后达到最大血浆浓度，约为370 ng/ml（大约690 nM）。估计的半衰期和清除率分别为6小时和70 ml/min/kg。由于圣约翰草提取物的治疗剂量远低于大鼠使用的剂量，因此开发了一种更灵敏的LC/MS/MS方法。该方法的定量下限为1 ng/ml。使用这种方法，在健康志愿者服用含有300 mg圣约翰草提取物（相当于14.8 mg金丝桃素）的薄膜包衣片后，可以监测血浆中金丝桃素的水平长达24小时。给药后3.5小时达到最大血浆浓度，约为150 ng/ml（大约280 nM）。半衰期和平均滞留时间分别为9小时和12小时。金丝桃素的药代动力学在提取物剂量达到600 mg时呈线性。将剂量增加到900或1200 mg提取物时，Cmax和AUC值低于从低剂量数据线性外推所预期的值。志愿者中的血浆浓度曲线很好地符合开放双室模型。在重复剂量研究中，未观察到血浆中金丝桃素的积累。使用重复剂量研究中的观察到的AUC值，估计在每日3次，每次300 mg提取物的正常治疗剂量方案下，金丝桃素的稳态血浆浓度大约为100 ng/ml（大约180 nM）。

After oral administration of 300 mg/kg Hypericum extract (WS 5572, containing 5% hyperforin) to rats maximum plasma levels of approximately 370 ng/ml (approx. 690 nM) were reached after 3 hr, as quantified by a HPLC and UV detection method. Estimated half-life and clearance values were 6 h and 70 ml/min/kg respectively. Since therapeutic doses of Hypericum extracts are much lower than that used in rats, a more sensitive LC/MS/MS method was developed. The lower limit of quantification of this method was 1 ng/ml. Using this method, plasma levels of hyperforin could be followed for up to 24 hr in healthy volunteers after administration of film coated tablets containing 300 mg hypericum extracts representing 14.8 mg hyperforin. The maximum plasma levels of approximately 150 ng/ml (approx. 280 nM) were reached 3.5 h after administration. Half-life and mean residence time were 9 and 12 hr respectively. Hyperforin pharmacokinetics were linear up to 600 mg of the extract. Increasing the doses to 900 or 1200 mg of extract resulted in lower Cmax and AUC values than those expected from linear extrapolation of data from lower doses. Plasma concentration curves in volunteers fitted well in an open two-compartment model. In a repeated dose study, no accumulation of hyperforin in plasma was observed. Using the observed AUC values from the repeated dose study, the estimated steady state plasma concentrations of hyperforin after 3 x 300 mg/day of the extract, i.e., after normal therapeutic dose regimen, was approximately 100 ng/ml (approx. 180 nM).

来源:Hazardous Substances Data Bank (HSDB)