(6R,7R,10R,11R,12E,17E,19E,21S)-6-[2-(diethylamino)ethylsulfonyl]-21-hydroxy-11,19-dimethyl-10-propan-2-yl-9,26-dioxa-3,15,28-triazatricyclo[23.2.1.03,7]octacosa-1(27),12,17,19,25(28)-pentaene-2,8,14,23-tetrone

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 大环内酯内酰胺
• 英文名称: (6R,7R,10R,11R,12E,17E,19E,21S)-6-[2-(diethylamino)ethylsulfonyl]-21-hydroxy-11,19-dimethyl-10-propan-2-yl-9,26-dioxa-3,15,28-triazatricyclo[23.2.1.03,7]octacosa-1(27),12,17,19,25(28)-pentaene-2,8,14,23-tetrone
• 化学式: C₃₄H₅₀N₄O₉S
• 分子量: 690.8
• InChiKey: SUYRLXYYZQTJHF-PSUTZUHDSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  48
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.62
• 拓扑面积：
  185
• 氢给体数：
  2
• 氢受体数：
  11

ADMET

代谢

奎奴普丁和达福普丁转化为几个主要活性代谢物：奎奴普丁有2个结合型代谢物（与谷胱甘肽和半胱氨酸结合）和达福普丁有1个非结合型代谢物（通过水解形成），这些代谢物与互补的母药协同作用。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，但升高率仅略高于安慰剂或对照药物。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疗程的情况下自行解决。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肝脏损伤的实例。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，没有发表的报告将其与肝炎或黄疸特异性地联系起来。因此，奎奴普丁和达福普丁引起的临床明显肝脏损伤可能发生，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已经证实，Synercid 显著抑制了细胞色素 P450 3A4 对环孢素 A、咪达唑仑、硝苯地平和特非那丁的代谢。此外，在接受 Synercid 7.5 mg/kg 每 8 小时一次，连续给药 2 天，并在第 3 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，应当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

辛尼西德（Synercid）和地高辛之间可能存在药物相互作用，但通过CYP3A4酶抑制发生的可能性不大。辛尼西德在体外对 Lentum 欧杆菌（Eubacterium lentum）展示了活性（在两个菌株上进行测试时的MIC值为0.25微克/毫升）。地高辛部分通过肠道中的细菌进行代谢，因此，基于辛尼西德对地高辛肠道代谢（通过 Lentum 欧杆菌）的抑制，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)