N-[(3S,6S,12R,15S,16R,19S)-25-[[(3S)-1-azabicyclo[2.2.2]octan-3-yl]sulfanylmethyl]-3-[[4-(dimethylamino)phenyl]methyl]-12-ethyl-4,16-dimethyl-2,5,11,14,18,21,24-heptaoxo-19-phenyl-17-oxa-1,4,10,13,20-pentazatricyclo[20.4.0.06,10]hexacosan-15-yl]-3-hydroxypyridine-2-carboxamide | 120138-50-3

• 物质功能分类: 生物化工 - 抑制剂
• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 肽模拟物
• 英文名称: N-[(3S,6S,12R,15S,16R,19S)-25-[[(3S)-1-azabicyclo[2.2.2]octan-3-yl]sulfanylmethyl]-3-[[4-(dimethylamino)phenyl]methyl]-12-ethyl-4,16-dimethyl-2,5,11,14,18,21,24-heptaoxo-19-phenyl-17-oxa-1,4,10,13,20-pentazatricyclo[20.4.0.06,10]hexacosan-15-yl]-3-hydroxypyridine-2-carboxamide
• CAS: 120138-50-3
• 化学式: C₅₃H₆₇N₉O₁₀S
• 分子量: 1022.2
• InChiKey: WTHRRGMBUAHGNI-MJWHERSYSA-N

物化性质

• 熔点：
  ~200°
• 物理描述：
  Solid
• 颜色/状态：
  White to slightly yellow powder
• 溶解度：
  In water, 6.7X10-3 mg/L at 25 °C (est)
• 蒸汽压力：
  1.51X10-43 mm Hg at 25 °C (est)
• 解离常数：
  pKa = 6.68 (pyridine) (est)

计算性质

• 辛醇/水分配系数(LogP)：
  4.2
• 重原子数：
  73
• 可旋转键数：
  10
• 环数：
  9.0
• sp3杂化的碳原子比例：
  0.53
• 拓扑面积：
  257
• 氢给体数：
  4
• 氢受体数：
  14

ADMET

代谢

奎奴普丁和达福普丁转化为几种主要活性代谢物：奎奴普丁有2种结合型代谢物（与谷胱甘肽和半胱氨酸结合）和达福普丁有1种非结合型代谢物（通过水解形成），这些代谢物与相应的母药也具有协同作用。这种转化是通过非酶促反应在体外发生的，独立于细胞色素P-450（CYP）和谷胱甘肽转移酶酶。

Quinupristin and dalfopristin are converted to several major active metabolites: 2 conjugated (with glutathione and cysteine) metabolites for quinupristin and one nonconjugated (formed by hydrolysis) metabolite for dalfopristin, which also act synergistically with the complementary parent drug. This conversion occurs in vitro by nonenzymatic reactions independent of cytochrome P-450 (CYP) and glutathione transferase enzymes.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 肝毒性

血清转氨酶水平升高在接受奎奴普丁和达福普丁治疗的患者中占有一定比例，但比安慰剂或对照药物的升高率要低得多。这些升高通常是轻到中度的，无症状且自限性，经常在不中断治疗甚至不中断治疗的情况下自行解决。超过上限正常值（ULN）5倍的升高发生在不到1%的患者中。奎奴普丁-达福普丁还可能引起直接胆红素和总胆红素的升高，但这些升高是轻微的，并未伴随血清酶的升高或其他肝脏损伤的证据。在许多奎奴普丁和达福普丁的临床试验中，没有可以确信归因于其使用的临床明显的肝脏损伤实例。接受奎奴普丁和达福普丁治疗的患者通常病情严重，败血症且正在接受多种药物或肠外营养，因此治疗期间出现的黄疸往往是多因素的，难以归因于特定原因。尽管如此，自从这种抗生素组合被批准并更广泛使用以来，没有公开发表的报告将其与肝炎或黄疸联系起来。因此，奎奴普丁和达福普丁引起的临床明显的肝脏损伤可能会发生，但非常罕见。

Elevations in serum aminotransferase levels occur in a proportion of patients receiving quinupristin and dalfopristin, but rates are minimally higher than with placebo or comparator drugs. The elevations are generally mild-to-moderate, asymptomatic and self-limited, frequently resolving without discontinuation or even interruption of therapy. Elevations above 5 times ULN occur in less than 1% of patients. Quinupristin-dalfopristin can also cause elevations in direct as well as total bilirubin, but these elevations are mild and not accompanied by elevations in serum enzymes or other evidence of liver injury. In the many clinical trials of quinupristin and dalfopristin there were no instances of clinically apparent liver injury that could be attributed convincingly to their use. Patients who receive quinupristin and dalfopristin are often severely ill, septic and receiving multiple medications or parenteral nutrition, so that jaundice arising during therapy is often multifactorial and difficult to assign to a specific cause. Nevertheless, since the approval and more wide spread use of this antibiotic combination, there have been no published reports of hepatitis or jaundice linked specifically to it use. Thus, clinically apparent liver injury from quinupristin and dalfopristin may occur, but is quite rare.

来源:LiverTox

毒理性

• 相互作用

Synercid与硝苯地平（重复口服剂量）和咪达唑仑（静脉推注剂量）联合给药在健康志愿者中导致这些药物的血药浓度升高。硝苯地平和咪达唑仑的Cmax分别增加了18%和14%（中值），AUC分别增加了44%和33%。

Concomitant administration of Synercid and nifedipine (repeated oral doses) and midazolam (intravenous bolus dose) in healthy volunteers led to elevated plasma concentrations of these drugs. The Cmax increased by 18% and 14% (median values) and the AUC increased by 44% and 33% for nifedipine and midazolam, respectively.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

体外药物相互作用研究表明，Synercid 显著抑制了细胞色素 P450 3A4 对环孢素 A、咪达唑仑、硝苯地平和特非那定的代谢。此外，在接受 Synercid 7.5 mg/kg 每 8 小时一次，连续两天给药，并在第三天给予 300 mg 环孢素的 24 名受试者中，环孢素的 AUC（药时曲线下面积）增加了 63%，环孢素的 Cmax（最大血药浓度）增加了 30%，环孢素的半衰期增加了 77%，环孢素的清除率下降了 34%。当环孢素与 Synercid 联用时，应进行环孢素的治疗水平监测。

In vitro drug interaction studies have demonstrated that Synercid significantly inhibits cytochrome P450 3A4 metabolism of cyclosporin A, midazolam, nifedipine and terfenadine. In addition, 24 subjects given Synercid 7.5 mg/kg q8h for 2 days and 300 mg of cyclosporine on day 3 showed an increase of 63% in the AUC of cyclosporine, an increase of 30% in the Cmax of cyclosporine, a 77% increase in the half life of cyclosporine, and, a decrease of 34% in the clearance of cyclosporine. Therapeutic level monitoring of cyclosporine should be performed when cyclosporine must be used concomitantly with Synercid.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

Synercid和地高辛之间的药物相互作用不能排除，但通过CYP3A4酶抑制发生的可能性不大。Synercid在体外对Eubacterium lentum展示了活性（在两个菌株上进行测试时的MIC值为0.25 ug/mL）。地高辛部分由肠道中的细菌代谢，因此，基于Synercid抑制地高辛的肠道代谢（由Eubacterium lentum）的药物相互作用是可能的。

A drug interaction between Synercid and digoxin cannot be excluded but is unlikely to occur via CYP3A4 enzyme inhibition. Synercid has shown in vitro activity (MICs of 0.25 ug/mL when tested on two strains) against Eubacterium lentum. Digoxin is metabolized in part by bacteria in the gut and as such, a drug interaction based on Synercid's inhibition of digoxin's gut metabolism (by Eubacterium lentum) may be possible.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

在一项病例报告中，一名21岁的女性肾移植受者在接受每日150毫克口服环孢素后，开始使用静脉注射20毫克/千克/日的奎奴普丁/达福普汀治疗，两天后环孢素血药水平升高。基线低谷环孢素水平在80至105纳克/毫升之间。开始奎奴普丁/达福普汀治疗两天和三天后，低谷环孢素水平分别升至261和291纳克/毫升。环孢素的剂量减少到每日100毫克，血药水平恢复到基线水平。在停用奎奴普丁/达福普汀后，环孢素血药浓度降低，剂量增加到了之前的方案。

A case is presented in which a 21-yr-old woman who was receiving 150 mg/day oral cyclosporine after kidney transplantation developed elevated cyclosporine blood levels 2 days after starting treatment with intravenous injections of 20 mg/kg/day quinupristin/dalfopristin. Baseline trough cyclosporine levels ranged from 80 to 105 ng/ml. Two and 3 days after initiation of quinupristin/dalfopristin therapy, trough cyclosporine levels increased to 261 and 291 ng/ml, respectively. The cyclosporine dosage was decreased to 100 mg/day and the blood levels returned to baseline. After discontinuation of quinupristin/dalfopristin, the cyclosporine blood concentration decreased and the dosage was increased to the previous regimen.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

奎奴普丁和达福普丁在大鼠乳汁中有分布...。

Quinupristin and dalfopristin is distributed into milk in rats ... .

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

喹努普里斯坦和达福普里斯坦的药代动力学在大鼠、猴子和人类中经过放射性标记和非标记药物的静脉输注后进行了研究。在大鼠和猴子中，喹努普里斯坦和达福普里斯坦在血液中迅速消除并广泛分布到组织中。然而，它们不会显著地渗透到中枢神经系统或穿过胎盘，并且在停止给药后似乎不会在体内显著残留。喹努普里斯坦在大鼠和猴子体内的血液消除半衰期分别约为0.6小时和0.5小时，而达福普里斯坦在大鼠和猴子体内的血液消除半衰期分别约为0.6小时和0.2小时。两种化合物主要通过胆汁进入粪便消除；喹努普里斯坦主要以原形排出，而达福普里斯坦在排出前会广泛代谢。代谢物包括对达福普里斯坦具有微生物活性的普里斯坦霉素PIIA，以及对喹努普里斯坦具有微生物活性的谷胱甘肽和半胱氨酸结合衍生物。喹努普里斯坦和达福普里斯坦在人体内似乎以相似的方式处理。静脉给药后，两种化合物都会迅速从血液中清除，喹努普里斯坦的消除半衰期约为1小时，达福普里斯坦的消除半衰期为0.4-0.5小时。喹努普里斯坦的药代动力学特征与剂量无关，达福普里斯坦和RP 12536也是如此。喹努普里斯坦/达福普里斯坦在人类非炎症性间质液中的血管外扩散已经进行了评估。

The pharmacokinetics of quinupristin/dalfopristin have been studied in rats, monkeys and humans following intravenous infusion of radiolabelled and unlabelled drug. In rats and monkeys quinupristin and dalfopristin undergo rapid elimination from the blood and wide tissue distribution. Nevertheless, they do not penetrate the central nervous system or cross the placenta to any significant degree and they do not appear to be subject to significant body retention following cessation of administration. The blood elimination half-life of quinupristin was approximately 0.6 hr in rats and 0.5 hr in monkeys, and that of dalfopristin was approximately 0.6 hr and 0.2 hr, respectively. Both compounds are primarily eliminated through the bile into the faeces; quinupristin is mainly excreted unchanged whereas dalfopristin is extensively metabolized beforehand. The metabolites include the microbiologically active pristinamycin PIIA for dalfopristin and the microbiologically active glutathione- and cysteine-conjugated derivatives for quinupristin. Quinupristin and dalfopristin appear to be handled in a similar manner by humans. Following intravenous administration both compounds are rapidly cleared from the blood with elimination half-lives of approximately 1 hr for quinupristin and 0.4-0.5 hr for dalfopristin. The pharmacokinetic profile of quinupristin is dose-independent and so is that of dalfopristin and RP 12536 when considered together. Extravascular diffusion of quinupristin/dalfopristin has been assessed in human non-inflammatory interstitial fluid.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

粪便排泄是母药及其代谢物的主要消除途径（占剂量的75至77%）。尿液排泄约占quinupristin的15%和dalfopristin的19%。大鼠的预临床数据显示，大约80%的剂量通过胆汁排泄，并提示在人体中，胆汁排泄可能是粪便消除的主要途径。

Fecal excretion constitutes the main elimination route for both parent drugs and their metabolites (75 to 77% of dose). Urinary excretion accounts for approximately 15% of the quinupristin and 19% of the dalfopristin dose. Preclinical data in rats have demonstrated that approximately 80% of the dose is excreted in the bile and suggest that in man, biliary excretion is probably the principal route for fecal elimination.

来源:Hazardous Substances Data Bank (HSDB)

制备方法与用途

链阳霉素制剂

**链阳霉素制剂（Quinupristin-dalfopristin，商品名：Synercid、辛内吉、森东西德）是一种半合成链阳菌素复方制剂。**该制剂含有两个普那霉素的半合成衍生物——达福普汀与奎努普汀。这两种成分可与细菌70s核糖体的50s亚基不可逆地结合，从而抑制细菌蛋白质的合成。

具体而言，当达福普汀与细菌核糖体结合后会引起核糖体构象改变，从而提高奎努普汀与核糖体的亲和力。复方制剂中，奎努普汀和达福普汀的血浆半减期分别为3小时和1小时；血浆Cmax分别为2.56 mg/ml和6.91 mg/ml；AUC分别为3.92 mg·h/ml和43.5 mg·h/ml。两者体内清除率大致相同，表现组织浓度也一致，主要经由粪便排泄。

本制剂主要用于治疗革兰氏阳性菌引起的皮肤及软组织感染、医院内获得性肺炎以及屎肠球菌引起的感染。

化学性质

链阳霉素为一种白色至类白色的固体，可溶于ethanol、methanol、DMSO和water，但水溶液不稳定。

用途与作用机制

奎奴普汀（Quinupristin）是一种链球菌素类抗生素，其化学式为120138-50-3。

作用机制

奎奴普汀通过阻断细菌核糖体亚基中肽键的合成来抑制细菌生长和繁殖。具体来说，它阻止多肽链的延伸过程，促进不完全蛋白链的分离。

在细菌细胞内，核糖体是负责蛋白质合成的重要结构，由两个亚基组成：一个负责肽键的形成，另一个负责多肽链的延伸。当细菌受到奎奴普汀的作用时，它会与核糖体亚基中的特定区域结合，从而干扰肽键的形成过程。这种干扰导致肽键无法正确形成，进而阻止了多肽链的延伸。

由于多肽链无法延伸，细菌细胞内的蛋白质合成过程被中断，导致细菌无法正常生长和繁殖，最终导致细菌死亡。此外，奎奴普汀还可以促进不完全蛋白链的分离，这意味着细菌细胞内的蛋白质合成不仅被中断，而且已经形成的蛋白质也无法正常发挥功能。

总之，奎奴普汀作为一种链球菌素类抗生素，通过阻断细菌核糖体亚基中肽键的合成来抑制细菌的生长和繁殖。其作用机制包括阻止多肽链的延伸和促进不完全蛋白链的分离，从而有效杀灭细菌并治疗感染疾病。