(2S,3S)-2,3-dihydroxybutanedioic acid;N,N-dimethyl-2-[6-methyl-2-(4-methylphenyl)imidazo[1,2-a]pyridin-3-yl]acetamide | 99294-93-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: (2S,3S)-2,3-dihydroxybutanedioic acid;N,N-dimethyl-2-[6-methyl-2-(4-methylphenyl)imidazo[1,2-a]pyridin-3-yl]acetamide
• CAS: 99294-93-6
• 化学式: C23H27N3O7
• 分子量: 457.5
• InChiKey: NYVVVBWEVRSKIU-WUUYCOTASA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.13
• 重原子数：
  33
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  153
• 氢给体数：
  4
• 氢受体数：
  8

ADMET

代谢

佐匹克隆和唑吡坦主要用作催眠药。两者都会被广泛代谢；佐匹克隆会发生N-去甲基化、N-氧化和脱羧反应，而唑吡坦会经历甲基氧化和咪唑吡啶环系统上一个位置的羟基化。由于已报道CYP3A4在唑吡坦代谢中发挥重要作用，因此应考虑与该CYP同种物的底物和/或抑制剂可能的相互作用。/未指定盐类/

... Zopiclone & zolpidem are used primarily as hypnotics. Both are extensively metabolized; N-demethylation, N-oxidation, & decarboxylation of zopiclone occur, & zolpidem undergoes oxidation of methyl groups & hydroxylation of a position on the imidazolepyridine ring system. ... Since CYP3A4 has been reported to play an important role in metab of zolpidem, possible interactions with drugs which are substrates &/or inhibitors of that CYP isozyme should be considered. /Salt not specified/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

氯丙嗪、氟哌啶醇、丙咪嗪和西咪替丁对唑吡坦的毒代动力学影响很小，尽管观察到当唑吡坦与氯丙嗪和丙咪嗪联合使用时，其镇静作用有所增强。与西咪替丁或雷尼替丁同时使用时，没有观察到药效学相互作用。/未指明盐类/

Chlorpromazine, haloperidol, imipramine, & cimetidine have little effect on zolpidem toxicokinetics, although potentiation of the sedative effect of zolpidem was observed when it was given in combination with chlorpromazine & imipramine. No pharmacodynamic interactions have been observed with concomitant admin of cimetidine or ranitidine. /Salt not specified/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

这项研究旨在确定催眠药唑吡坦和抗抑郁药舍曲林之间是否存在药代动力学（PK）相互作用。28名健康的女性志愿者接受了单独一次剂量的唑吡坦，以及在连续5天中，在舍曲林50毫克长期剂量（持续19天）的条件下，每次10毫克的唑吡坦。使用高效液相色谱法（HPLC）测定了整个研究过程中不同时间点的唑吡坦、舍曲林和N-去甲基舍曲林的血浆水平，并由此推导出PK参数。与单独使用唑吡坦相比，在舍曲林存在时，第一剂唑吡坦的半衰期缩短，第五剂唑吡坦的Cmax显著增加，其Tmax显著减少。在服用5剂唑吡坦后，舍曲林的AUC（减少60%）和N-去甲基舍曲林的Cmax（增加13%）发生了变化。唑吡坦对第二天数字符号替换测试没有影响，并且两种药物均耐受性良好。总体而言，舍曲林50毫克与唑吡坦10毫克的联合用药在健康女性中似乎是安全的，但可能会导致唑吡坦的作用起始时间缩短和效果增加。/未指定盐类/

This study was undertaken to determine whether there are pharmacokinetic (PK) interactions between zolpidem, a hypnotic, & sertraline, an antidepressant. 28 healthy female volunteers received a single dose of zolpidem alone & 5 consecutive dose(s) of zolpidem 10 mg in the presence of chronic doses (19 days) of sertraline 50 mg. Using HPLC, plasma levels of zolpidem, sertraline, & N-desmethylsertraline were determined at different times throughout the study & PK parameters derived. Compared to zolpidem alone, the /half life/ of the first dose of zolpidem in the presence of sertraline was reduced, the Cmax of the fifth zolpidem dose in the presence of sertraline was significantly increased, & its Tmax was significantly reduced. After 5 doses of zolpidem, the AUC of sertraline (-60%) & the Cmax of N-desmethylsertraline (+13%) were changed. There were no next-day effects of zolpidem on the Digit Symbol Substitution Test, & both drugs were well tolerated. Overall, coadministration of sertraline 50 mg & zolpidem 10 mg appears to be safe in healthy females but could result in a shortened onset of action & increased effect of zolpidem. /Salt not specified/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

利托那韦对安眠药三唑仑和唑吡坦生物转化的抑制作用在体外使用人肝微粒体进行了测试。在一项双盲临床研究中，志愿者研究受试者同时接受了0.125毫克三唑仑或5.0毫克唑吡坦，并伴有低剂量利托那韦（200毫克，4剂），或安慰剂。利托那韦在体外对三唑仑羟基化有很强的抑制作用，但对唑吡坦羟基化的抑制作用较弱。在临床研究中，利托那韦将三唑仑的清除率降低到小于对照组的4%（p<0.005），延长了消除半衰期（41小时对3小时；p<0.005），并放大了苯二氮䓬类药物的激动剂效果，如镇静和性能损害。相比之下，利托那韦将唑吡坦的清除率降低到对照组的78%（p<0.08），并稍微延长了消除半衰期（2.4小时对2.0小时；无统计学意义）。唑吡坦的苯二氮䓬类药物激动剂效果并未因利托那韦而改变。短期低剂量利托那韦的给药显著地损害了三唑仑的清除率并增强了临床效果。相比之下，利托那韦对唑吡坦清除率的影响较小，临床上不重要。这些发现与三唑仑清除率完全依赖CYP3A活性，而唑吡坦清除率部分依赖CYP3A的情况一致。/未指定盐类/

... The inhibitory effect of ritonavir on the biotransformation of the hypnotic agents triazolam & zolpidem was tested in vitro using human liver microsomes. In a double-blind clinical study, volunteer study subjects received 0.125 mg triazolam or 5.0 mg zolpidem concurrent with low-dose ritonavir (4 doses of 200 mg), or with placebo. ... Ritonavir was a potent in vitro inhibitor of triazolam hydroxylation but was less potent as an inhibitor of zolpidem hydroxylation. In the clinical study, ritonavir reduced triazolam clearance to <4% of control values (p<.005), prolonged elimination half-life (41 versus 3 hrs; p<.005), & magnified benzodiazepine agonist effects such as sedation & performance impairment. In contrast, ritonavir reduced zolpidem clearance to 78% of control values (p<.08), & slightly prolonged elimination half-life (2.4 versus 2.0 hrs; NS). Benzodiazepine agonist effects of zolpidem were not altered by ritonavir. ... Short-term low-dose admin of ritonavir produces a large & significant impairment of triazolam clearance & enhancement of clinical effects. In contrast, ritonavir produced small & clinically unimportant reductions in zolpidem clearance. The findings are consistent with the complete dependence of triazolam clearance on CYP3A activity, compared with the partial dependence of zolpidem clearance on CYP3A. /Salt not specified/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

目标是对重复夜间使用佐匹克隆和氟西汀的可能的药代动力学和药效学相互作用进行评估。29名健康女性志愿者（平均年龄，25.6岁）接受了佐匹克隆（10毫克）和氟西汀（20毫克）的开放式设计：第1个晚上服用佐匹克隆，随后是1天的清洗期，第3-27天每天早上服用氟西汀，第28-32天早上服用氟西汀加晚上服用佐匹克隆。在从一个方案转换到下一个方案时，测定佐匹克隆、氟西汀和去甲氟西汀的血浆水平。在第1、2、28、29和33天进行了早晨的精神运动测试。在氟西汀给药的第24天达到了氟西汀/去甲氟西汀的稳态血浆浓度。在氟西汀和去甲氟西汀的任何药代动力学参数方面，第27天和第32天之间没有显著差异。在佐匹克隆血浆浓度的第1、28和32个晚上之间，AUC（药时曲线下面积）、最大血浆浓度或达到最大浓度的时间参数没有显著差异。与第28个晚上相比，第32个晚上的佐匹克隆的半衰期统计学上有显著增加（分别为3.64小时和3.29小时）。在整个研究过程中，次日早晨的数字符号替换测试表现没有显著差异。佐匹克隆和氟西汀单独使用或联合使用时均能很好地耐受。这些发现表明，在健康女性中共用氟西汀和佐匹克隆（连续5剂）时，不存在具有临床意义的药代动力学或药效学相互作用。因此，基于这些观察，短期联合使用氟西汀（20毫克）和佐匹克隆（10毫克）似乎是安全的。/未指明盐类/

The objective was to evaluate possible pharmacokinetic & pharmacodynamic interactions for repeated nightly zolpidem dosing with fluoxetine. 29 healthy female volunteers (mean age, 25.6 yrs) received zolpidem (10 mg) & fluoxetine (20 mg) in the following open design: zolpidem on night 1 followed by 1 washout day, a daily morning dose of fluoxetine on days 3-27, & a morning dose of fluoxetine plus an evening dose of zolpidem on days 28-32. Plasma levels of zolpidem, fluoxetine, & norfluoxetine were determined at the transitions from one regimen to the next. Morning psychomotor tests were performed on days 1, 2, 28, 29, & 33. Steady-state plasma concns of fluoxetine/norfluoxetine were reached by day 24 of fluoxetine dosing. No significant differences in any pharmacokinetic parameters for fluoxetine & norfluoxetine were observed between day 27 & day 32. There were no significant differences in AUC, maximal plasma concn, or time to maximal concn parameters for zolpidem plasma concns among nights 1, 28, & 32. There was a statistically significantly increased /half life/ for zolpidem on night 32, compared with night 28 (3.64 & 3.29 hr, respectively). There were no significant differences in the next-morning Digit Symbol Substitution Test performance at any time in the study. Both zolpidem & fluoxetine were well tolerated alone or during coadministration. These findings indicate the absence of clinically significant pharmacokinetic or pharmacodynamic interactions between fluoxetine & zolpidem (5 consecutive doses) when the drugs are coadministered to healthy women. Therefore, based on these observations, short-term cotherapy with fluoxetine (20 mg) & zolpidem (10 mg) appears safe. /Salt not specified/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

治疗应主要是对症和支持性的，类似于苯二氮卓类药物过量的治疗。... 必须提供气管保护。在一例患者中使用了活性炭，但没有系统性的研究支持其使用。体外治疗方法（血液透析，血液灌注）在临床设置中可能不会有用（高蛋白结合，快速起效和消除，有有效的解毒剂）。在一项对照研究中，氟马西尼... 快速逆转了由唑吡坦引起的警觉性、心理测量性和脑电图变化。在一例过量服用300毫克唑吡坦后出现昏迷、针尖样瞳孔和需要辅助通气的呼吸抑制的患者中，静脉注射氟马西尼... 后患者苏醒，瞳孔缩小得到纠正，呼吸模式和血气分析恢复正常。纳洛酮似乎对减轻昏迷或呼吸性酸中毒无效。可能需要重复使用氟马西尼。/未指明盐类/

Treatment should be largely symptomatic & supportive, similar to that following a benzodiazepine overdose. ... Tracheal protection must be provided. Activated charcoal was used in one patient, but there are no systematic studies supporting its use. Extracorporeal methods of treatment (hemodialysis, hemoperfusion) would probably not be useful in the clinical setting (high protein binding, rapid onset of action & elimination, availability of an effective antidote). In a controlled study flumazenil ... rapidly reversed the decr in alertness, psychometricity, & electroencephalographic changes induced by zolpidem. In one overdose patient who had ingested 300 mg of zolpidem followed by coma, pinpoint pupils, & respiratory depression requiring assisted ventilation, iv flumazenil ... was followed by arousal of the patient, correction of the miosis, & normalization of the respiratory pattern & blood gas analysis. Naloxone appears to be ineffective in diminishing coma or respiratory acidosis. Repeated doses of flumazenil may be required. /Salt not specified/

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

口服20毫克唑吡坦后，30分钟达到血药峰浓度200 ng/mL。唑吡坦口服给药后，从胃肠道快速且完全吸收。尽管药物在首次通过肝脏时会发生一定生物转化，导致生物利用度大约为70%，但在7-20毫克的剂量下，唑吡坦有92%与血浆蛋白结合。静脉注射5毫克剂量的表观分布容积为0.5 L/kg。大脑中的浓度达到血浆中浓度的三分之一到一半。唑吡坦被完全代谢，给药剂量的不到1%以原形从尿液中排出。已经鉴定出三种代谢物，但在静脉注射8毫克剂量后没有药理活性。唑吡坦的系统清除率为0.26 L/kg/g，消除半衰期为1.5小时。/未指定盐类/

A peak blood level of 200 ng/mL was reached 30 min after oral admin of 20 mg zolpidem. After oral admin zolpidem is rapidly & completely absorbed from the GI tract. Although some first-pass biotransformation of the drug results in a bioavailability of about 70%, after doses of 7-20 mg, zolpidem is 92% bound to plasma proteins. The apparent volume of distribution after a 5 mg iv dose was 0.5 L/kg. Brain concns reach one third to one half of those achieved in the plasma. Zolpidem is completely metabolized. <1% of an admin dose is excreted unchanged in the urine. Three metabolites have been identified but have no pharmacologic activity after an 8 mg iv dose. Systemic clearance of zolpidem was 0.26 L/kg/g & the elimination half-life was 1.5 hr. /Salt not specified/

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

唑吡坦在母乳中的排泄量占给药剂量的0.004%至0.019%。/未指明盐类/

The excretion of zolpidem in breast milk represents 0.004 to 0.019% of an admin dose. /Salt not specified/

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

唑吡坦几乎完全通过在肝脏转化为无活性产物而被消除，主要是通过将苯基和咪唑并吡啶环上的甲基氧化成相应的羧酸。在具有正常肝血流或功能的个体中，其在血浆中的半衰期大约为2小时。在肝硬化患者中，这个值可能会增加两倍或更多，而且在老年患者中也往往更高；在这两类患者中常常需要调整剂量。尽管尿液中几乎找不到未改变的唑吡坦，但药物的消除在慢性肾衰竭患者中较慢，这主要是由于其表观分布容积的增加。/未指定盐类/

Zolpidem is eliminated almost entirely by conversion to inactive products in the liver, largely through oxidation of the methyl groups on the phenyl & imidazopyridine rings to the corresponding carboxylic acids. Its half-life in plasma is approx 2 hr in individuals with normal hepatic blood flow or function. This value may be increased twofold or more in those with cirrhosis, & it also tends to be greater in older patients; adjustment of dosage often is necessary in both categories of patients. Although little or no unchanged zolpidem is found in the urine, the elimination of the drug is slower in patients with chronic renal insufficiency, largely owing to an incr in its apparent volume of distribution. /Salt not specified/

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

固体分散体和Zolpidem在聚乙二醇4000（PEG 4000）和6000（PEG 6000）中的物理混合物被制备出来，目的是为了提高其水溶性。物理测定/显示/没有药物-聚合物相互作用...药物在这些配方中的溶解度和溶解速率都有所提高。基于PEG的配方的每个个别溶解曲线符合Baker-Lonsdale和一级动力学模型。最后，观察到Zolpidem口服给药时，作为单独药物悬浮液和作为固体分散体或物理混合物之间的共济失调诱导时间有显著差异。这些配方实际上显示出几乎2到3倍的更长共济失调诱导时间，这表明在PEG存在的情况下，肠道膜透性可能是吸收过程的限速因素。/未指明盐类/

Solid dispersions & physical mixtures of Zolpidem in polyethylene glycol 4000 (PEG 4000) & 6000 (PEG 6000) were prepared with the aim to incr its aqueous solubility. ... Physical determinations/revealed/ no drug-polymer interactions ... Both solubility & dissolution rate of the drug in these formulations were increased. Each individual dissolution profile of PEG based formulation fitted Baker-Lonsdale & first order kinetic models. Finally, significant differences in ataxic induction time were observed between Zolpidem orally administered as suspension of drug alone & as solid dispersion or physical mixture. These formulations, indeed, showed almost 2- to 3-fold longer ataxic induction times suggesting that, in the presence of PEG, the intestinal membrane permeability is probably the rate-limiting factor of the absorption process. /Salt not specified/

来源:Hazardous Substances Data Bank (HSDB)