雷特格韦 | 518048-05-0

• 物质功能分类: 原料药 - 人工合成抗感染类药 - 抗病毒类药
• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 中文名称: 雷特格韦
• 中文别名: N-(2-(4-(4-氟苄基氨基甲酰基)-5-羟基-1-甲基-6-氧代-1,6-二氢嘧啶-2-基)丙-2-基)-5-甲基-1,3,4-恶二唑-2-甲酰胺；拉替拉韦
• 英文名称: raltegravir
• 英文别名: RAL；MK-0518；N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-(1-methyl-1-{[(5-methyl-1,3,4-oxadiazol-2-yl)carbonyl] amino}ethyl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide；N-[2-[4-[(4-fluorophenyl)methylcarbamoyl]-5-hydroxy-1-methyl-6-oxopyrimidin-2-yl]propan-2-yl]-5-methyl-1,3,4-oxadiazole-2-carboxamide
• CAS: 518048-05-0
• 化学式: C₂₀H₂₁FN₆O₅
• 分子量: 444.422
• InChiKey: CZFFBEXEKNGXKS-UHFFFAOYSA-N

物化性质

• 熔点：
  216 °C(Solv: isopropanol (67-63-0))
• 密度：
  1.46±0.1 g/cm3(Predicted)
• 溶解度：
  可溶于DMSO（轻微）、甲醇（非常轻微）
• 蒸汽压力：
  4.5X10-22 mm Hg at 25 °C (est)

计算性质

• 辛醇/水分配系数(LogP)：
  1.1
• 重原子数：
  32
• 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：
  150
• 氢给体数：
  3
• 氢受体数：
  9

ADMET

代谢

肝脏 (UGT1A1)

Hepatic (UGT1A1)

来源:DrugBank

代谢

在粪便中，仅检测到拉替拉韦，其中大部分可能源于胆汁中分泌的拉替拉韦葡萄糖醛酸酯的水解，如前临床物种所观察到的。在尿液中检测到两个成分，即拉替拉韦和拉替拉韦葡萄糖醛酸酯，分别约占剂量的9%和23%。主要循环实体是拉替拉韦，约占总放射性的70%；血浆中剩余的放射性由拉替拉韦葡萄糖醛酸酯组成。

In feces, only raltegravir was present, most of which is likely derived from hydrolysis of raltegravir-glucuronide secreted in bile as observed in preclinical species. Two components, namely raltegravir and raltegravir-glucuronide, were detected in urine and accounted for approximately 9 and 23% of the dose, respectively. The major circulating entity was raltegravir and represented approximately 70% of the total radioactivity; the remaining radioactivity in plasma was accounted for by raltegravir-glucuronide.

来源:Hazardous Substances Data Bank (HSDB)

代谢

使用选择性化学抑制剂和cDNA表达的UDP-葡萄糖醛酸基转移酶（UGT）的研究表明，UGT1A1是主要负责形成拉替拉韦葡萄糖苷酶的酶。因此，数据表明，人体清除拉替拉韦的主要机制是UGT1A1介导的葡萄糖苷酸化。

Studies using isoform-selective chemical inhibitors and cDNA-expressed UDP-glucuronosyltransferases (UGT) show that UGT1A1 is the main enzyme responsible for the formation of raltegravir-glucuronide. Thus, the data indicate that the major mechanism of clearance of raltegravir in humans is UGT1A1-mediated glucuronidation.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 肝毒性

在大规模临床试验中，使用多替拉韦治疗与丙氨酸转氨酶（ALT）升高超过正常上限（ULN）的3倍有关，发生在2%至5%的患者中，但这些比率与接受匹配的背景优化抗逆转录病毒治疗（不含多替拉韦）的对照组相似。这些升高并未伴随临床症状，通常不需要调整剂量。在多替拉韦的注册试验中描述了几例伴有黄疸的急性肝损伤的实例，这些情况与超敏反应有关，并在停药后得到解决。这些病例的临床特征并未提供，它们与多替拉韦的关系相对于同时使用的抗逆转录病毒药物并未完全确定。然而，自从多替拉韦获得批准并更广泛使用以来，出现了几例归因于多替拉韦的急性肝炎的病例报告。发病潜伏期从1个月到8个月不等，血清酶升高的模式是肝细胞型。没有出现免疫过敏和自身免疫特征。至少有一例已发表的病例导致了急性肝衰竭并需要肝移植。多替拉韦的产品标签提到肝炎和肝衰竭作为潜在的副作用，并指出患有乙型或丙型肝炎共感染的患者在开始多替拉韦治疗时容易恶化或肝炎发作，可能是免疫重建综合症的结果。建议在开始包含多替拉韦的治疗方案的患者中监测肝功能测试。

In large clinical trials, therapy with dolutegravir was associated with alanine aminotransferase (ALT) elevations of greater than 3 times the upper limit of normal (ULN) in 2% to 5% of patients, but these rates were similar to those in comparator groups receiving matched background optimized antiretroviral therapy without dolutegravir. These elevations were not associated with clinical symptoms and generally did not require dose modification. A few instances of acute liver injury with jaundice were described in the registration trials for dolutegravir which occurred in association with hypersensitivity reactions and resolved with drug discontinuation. The clinical features of these cases were not provided and their association with dolutegravir as opposed to the concurrent antiretroviral agents was not fully established. Since its approval and more wide spread use, however, several case reports of acute hepatitis attributable to dolutegravir have appeared. The latency to onset varried from 1 to 8 months and the pattern of serum enzyme elevations was hepatocellular. Immunoallergic and autoimmune features were not present. At least one published case resulted in acute liver failure and need for liver transplanation. The product label for dolutegravir mentions hepatitis and hepatic failure as potential adverse reactions and states that patients with hepatitis B or C coinfection are susceptible to worsening or flares of hepatitis with initiation of dolutegravir therapy, perhaps as a consequence of immune reconstitution syndrome. Monitoring of liver tests is recommended in patients starting regimens that include dolutegravir.

来源:LiverTox

毒理性

• 肝毒性

在大规模临床试验中，使用拉替拉韦治疗与丙氨酸转氨酶（ALT）升高相关，高达10%的患者出现升高，3%至4%的患者升高超过正常上限（ULN）的5倍，但这些比率与接受匹配的背景优化抗逆转录病毒治疗（不含拉替拉韦）的对照组相似。这些升高没有伴随临床症状，通常不需要调整剂量。目前还没有公开发表的报告将明显的肝脏损伤归因于拉替拉韦。尽管如此，拉替拉韦的产品标签提到了肝炎和肝衰竭作为潜在的副作用，但没有具体细节。拉替拉韦还与史蒂文斯-约翰逊综合征和药物过敏反应有关，这些反应可能伴有肝脏受累。最后，开始使用拉替拉韦进行抗逆转录病毒治疗可能导致免疫重建综合征，这可能会加重或激发共感染慢性乙型或丙型肝炎的发作。

In large clinical trials, therapy with raltegravir was associated with alanine aminotransferase (ALT) elevations in up to 10% and elevations of greater than 5 times the upper limit of normal (ULN) in 3% to 4% of patients, but these rates were similar to those in comparator groups receiving matched background optimized antiretroviral therapy without raltegravir. These elevations were not associated with clinical symptoms and generally did not require dose modification. There have been no published reports of clinically apparent cases of liver injury attributed to raltegravir. Nevertheless, the product label for raltegravir mentions hepatitis and hepatic failure as a potential adverse reactions, but without specific details. Raltegravir has also been linked to instances of Stevens Johnson syndrome and drug hypersensitivity reactions, which can be accompanied by hepatic involvement. Finally, initiation of antiretroviral therapy with raltegravir can result in the immune reconstitution syndrome which may cause a worsening or flare of an accompanying chronic hepatitis B or C in coinfected individuals.

来源:LiverTox

毒理性

• 肝毒性

在大规模临床试验中，使用比克替拉韦与恩曲他滨和替诺福韦艾拉酚胺联合治疗与丙氨酸转氨酶（ALT）升高（超过正常上限1.5倍）相关，在11%的患者中出现，但这些比率与接受匹配的背景优化抗逆转录病毒治疗（不含比克替拉韦）的比较组（12%至15%）相似。超过5倍正常上限的升高仅在1.4%的比克替拉韦治疗者中出现，而在对照组受试者中为0.9%至1.3%。这些升高与临床症状无关，通常不需要调整剂量。此外，没有出现急性肝细胞损伤和黄疸的病例。比克替拉韦的产品标签提到，当停止使用比克替拉韦与恩曲他滨和替诺福韦联合治疗时，可能会出现急性乙型肝炎加重和肝衰竭作为潜在的不良反应。这种不良反应可能在停止任何对HBV有同时活性的抗逆转录病毒方案时发生，并代表替诺福韦和恩曲他滨的效果。然而，自从其获得批准和更广泛使用以来，没有已发表的报告中明确将肝脏损伤或乙型肝炎加重的临床明显病例归因于比克替拉韦。

In large clinical trials, therapy with bictegravir combined with emtricitabine and tenofovir alafenamide was associated with alanine aminotransferase (ALT) elevations (above 1.5 times ULN) in 11% patients, but these rates were similar to those in comparator groups (12% to 15%) receiving matched background optimized antiretroviral therapy without bictegravir. Elevations above 5 times ULN occurred in only 1.4% of bictegravir vs 0.9% to 1.3% of control comparator arm subjects. The elevations were not associated with clinical symptoms and generally did not require dose modification. In addition, there were no instances of acute hepatocellular liver injury with jaundice. The product label for bictegravir mentions acute exacerbations of hepatitis B and hepatic failure as potential adverse reactions when bictegravir with emtricitabine and tenofovir is discontinued. This adverse reaction can occur upon discontinuation of any antiretroviral regimen with concurrent activity against HBV and represents the effects of tenofovir and emtricitabine. Nevertheless, since its approval and its more widescale use, there have been no published reports of clinically apparent cases of liver injury or exacerbation of hepatitis B convincingly attributed to bictegravir.

来源:LiverTox

毒理性

• 药物性肝损伤

raltegravir

Compound:raltegravir

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

DILI 注解：最令人关注的药物性肝损伤

DILI Annotation:Most-DILI-Concern

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

吸收、分配和排泄

• 吸收

从胃肠道吸收。

Absorbed from the gastrointestinal tract.

来源:DrugBank

吸收、分配和排泄

• 消除途径

粪便和尿液

Feces and urine

来源:DrugBank

吸收、分配和排泄

• 分布容积

大约83%与人类血浆蛋白结合，并且极少量分布到红细胞中（血液到血浆的分配比率为0.6）。

Approximately 83% bound to human plasma protein and is minimally distributed into red blood cells (blood-to-plasma partitioning ratio of 0.6).

来源:DrugBank

吸收、分配和排泄

• 清除

人体清除拉替拉韦的主要机制是经由UGT1A1介导的葡萄糖醛酸化，未改变药物的肾清除是拉替拉韦消除的次要途径（占总剂量的9%）。

The major mechanism of clearance of raltegravir in humans is glucuronidation mediated by UGT1A1, the renal clearance of unchanged drug is a minor pathway of elimination of raltegravir (9% of total dose).

来源:DrugBank

吸收、分配和排泄

Raltegravir（薄膜包衣片）在空腹状态下服用后大约3小时达到最大血药浓度（Tmax）。Raltegravir的药时曲线下面积（AUC）和最大血药浓度（Cmax）在100毫克至1600毫克的剂量范围内呈剂量比例增加。Raltegravir的12小时血药浓度（C12hr）在100毫克至800毫克的剂量范围内呈剂量比例增加，在100毫克至1600毫克的剂量范围内增加幅度略小于剂量比例。

Raltegravir (film-coated tablet) is absorbed with a Tmax of approximately 3 hours postdose in the fasted state. Raltegravir AUC and Cmax increase dose proportionally over the dose range 100 mg to 1600 mg. Raltegravir C12hr increases dose proportionally over the dose range of 100 to 800 mg and increases slightly less than dose proportionally over the dose range 100 mg to 1600 mg.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险性防范说明：
  P261,P305+P351+P338
• 危险性描述：
  H302,H315,H319,H335
• 储存条件：
  | 2~8℃ |

制备方法与用途

雷特格韦片简介

美国默克公司的雷特格韦片是第一个HIV整合酶链转移抑制剂（IntEGRAse STRAnd TRAnsfer Inhibitors, ISTI），也被称为MK-0518。它可以与多种抗逆转录病毒药物联合用药，用于治疗人类免疫缺陷病毒(HIV)-1感染。通过抑制病毒复制所需的HIV整合酶，雷特格韦能够减缓HIV-1感染的发生。

药理作用

当雷特格韦与其他抗HIV药物联合使用时，可以减少血液中的HIV数量，并增加称为CD4+T细胞的白细胞数量，从而有助于对抗其他感染。与利托那韦、依法韦仑、替拉那韦、泰诺福韦等药物相互作用的研究表明，雷特格韦对这些抗病毒药物无交叉耐药性，并且可以与其他多种药物产生协同作用。

不良反应

最常见的不良反应包括腹泻、恶心和头痛。此外，血液检查发现一些服用该药物的患者肌酶异常升高。

生物活性

RAltEGRAvir (MK-0518) 是一种有效的整合酶抑制剂，在无细胞试验中对野生型(WT) 和 S217Q PFV IN 的 IC50 分别为 90 nM 和 40 nM。它对HIV-1 IN 的选择性远高于其他相关 Mg2+依赖性酶，如 HCV 聚合酶、HIV 反转录酶和 HIV RNaseH。

靶点

• 整合酶 (S217Q PFV) （无细胞试验）：40 nM
• 整合酶 (WT PFV) （无细胞试验）：90 nM

体外研究

PFV整合携带 S217H 替换的IN后，对RAltEGRAvir 的敏感性降低10倍，IC50为900 nM。PFV IN 具有10% WT 活性且被 RAltEGRAvir 抑制，IC50 为200 nM，说明与 WT IN 相比，对整合酶（IN）链转移抑制剂(INSTI) 的敏感性降低约2倍。S217Q PFV IN 对RAltEGRAvir的敏感性至少与WT酶相似。

RAltEGRAvir 由葡萄糖醛酸化生成，并非通过肝脏代谢。在体外作用于人类T淋巴细胞培养物时，RAltEGRAvir有效抑制HIV-1达95%，浓度为31±20 nM。该药物对CEMx174 细胞也有效作用，IC95 为6 nM。RAltEGRAvir的主要代谢途径是葡萄糖醛酸化。强诱导剂UGT1A1显著降低其浓度。RAltEGRAvir微弱抑制肝细胞色素P450，并不会诱导CYP3A4 RNA 表达或CYP3A4依赖的睾丸激素6-β-羟化酶活性。

在镁和钙存在的情况下，RAltEGRAvir 的细胞扩散性降低。该药物及其相关的HIV-1整合酶(IN) 链转移抑制剂(INSTIs)高效阻断病毒复制。RALTEGRAVIR 作用于急性感染人类淋巴 CD4+ 淋巴细胞。

体内研究

在携带 SIVmac251 的非人类灵长类动物中，RAltEGRAvir 提高了病毒-免疫状态。单独给予该药物后，在非人类灵长类动物中未检测到病毒载量。