(8R)-3-[(4R,5S)-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7,8-dihydro-4H-imidazo[4,5-d][1,3]diazepin-8-ol

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 咪唑二氮卓类
• 英文名称: (8R)-3-[(4R,5S)-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7,8-dihydro-4H-imidazo[4,5-d][1,3]diazepin-8-ol
• 化学式: C₁₁H₁₆N₄O₄
• 分子量: 268.27
• InChiKey: FPVKHBSQESCIEP-JSXQXQAOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -2.1
• 重原子数：
  19
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.64
• 拓扑面积：
  112
• 氢给体数：
  4
• 氢受体数：
  6

ADMET

毒理性

• 肝毒性

在临床试验中，高达25%接受喷托司汀治疗的患者的血清酶水平升高，但这些异常通常是轻微和短暂的，很少需要调整剂量。喷托司汀引起的临床上明显的肝损伤是罕见的，但在成人和儿童中都有描述到严重肝损伤迅速导致多器官衰竭和死亡的显著案例。发病时间从几天到六个月不等。在这些病例中，休克、缺血、机会性感染和败血症的可能作用并不总是很好地定义。已经描述了肝细胞和胆汁淤积模式的酶升高。免疫过敏特征和自身抗体并不典型。

In clinical trials, serum enzymes elevations occurred in up to 25% of patients receiving pentostatin, but the abnormalities were generally mild and transient and rarely required dose modification. Clinically apparent liver injury from pentostatin is rare, but striking instances of severe liver injury leading rapidly to multiorgan failure and death have been described both in adults and children. The time to onset varied from a few days to six months. The possible role of shock, ischemia, opportunistic infections and sepsis in these cases has not always been well defined. Both hepatocellular and cholestatic patterns of enzyme elevations have been described. Immunoallergic features and autoantibodies were not typical.

来源:LiverTox

毒理性

毒性数据：小鼠（静脉注射）：LD50 122毫克/千克

ToxicityData:Mouse(iv): LD50 122 mg/kg

来源:NCI Investigational Drugs

毒理性

• 相互作用

有限的数据表明，同时使用喷托司汀（每两周4毫克/平方米）和氟达拉滨（主要是每28天间隔，每天10毫克/平方米，连续4天），一种合成嘌呤核苷酸，可能与严重和/或致命的肺毒性（例如，肺炎）有关。在一项研究中，6名同时接受这两种药物治疗难治性慢性淋巴细胞白血病的患者中，有4名患者据报道出现了这种毒性。

Limited data suggest that concomitant therapy with pentostatin (4 mg/sq m every 2 weeks) and fludarabine (principally 10 mg/sq m daily for 4 days at 28 day intervals), a synthetic purine nucleoside, may be associated with severe and/or fatal pulmonary toxicity (eg, pneumonitis). In one study, 4 of 6 patients receiving the drugs concomitantly for treatment of refractory chronic lymphocytic leukemia reportedly developed such toxicity.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

尽管使用本妥司他汀或别嘌醇单独治疗已与皮疹发展有关，但有限的证据表明，与单独使用本妥司他汀相比，在难治性毛细胞白血病患者中联合使用这两种药物，并未与皮疹发生率的增加有关。然而，其他毒性反应，包括肾脏或肝脏功能异常，在少数同时接受本妥司他汀和别嘌醇治疗的患者中已被观察到。据报道，一名患者在同时接受本妥司他汀和别嘌醇治疗期间发展出了致命的超敏性血管炎；然而，尚未建立与这些药物的因果关系。

Although therapy with either pentostatin or allopurinol alone has been associated with the development of skin rash, limited evidence suggests that concomitant use of the drugs, compared with pentostatin therapy alone, in patients with refractory hairy cell leukemia is not associated with an increased incidence of rash. However, other toxicities, including abnormalities in renal or hepatic function, have been observed in a few patients receiving concomitant pentostatin and allopurinol. ... One patient reportedly developed a fatal hypersensitivity vasculitis while receiving pentostatin and allopurinol concurrently; however, a causal relationship to the drugs has not been established.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

彭托司坦抑制了阿糖腺苷的降解，并在细胞培养和实验性诱导的白血病动物中增强了其细胞毒性。此外，对急性白血病患者有限的资料显示，与彭托司坦单药治疗相比，联合治疗可能与增加的血浆阿糖腺苷浓度和/或半衰期以及更大的毒性相关。尽管有报道称，在接受阿糖腺苷和彭托司坦同时治疗的急性T细胞淋巴细胞性白血病患者中，有少数患者出现了改善和/或缓解。

Pentostatin inhibits the degradation of vidarabine and enhances its cytotoxicity in cell culture and in animals with experimentally induced leukemia. In addition, limited data in patients with acute leukemia suggest that combined therapy with the drugs may be associated with increased plasma vidarabine concentrations and/or half-life and greater toxicity compared with pentostatin therapy alone. Although improvement and/or remission has been reported in a few patients with acute T cell lymphoblastic leukemia who received vidarabine and pentostatin concomitantly.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

经静脉注射0.25 mg/kg剂量的戊多司坦，每日一次，连续4或5天，对数量有限的晚期难治性癌症患者进行治疗，其血药浓度大约在3.2-9.7 ng/ml之间。血药浓度似乎与剂量呈线性增加；在一项针对白血病患者的研究中，给予0.25或1 mg/kg剂量的药物，以30分钟静脉输注的方式给药，1小时后测定的血中戊多司坦浓度分别平均约为0.4或1.26 μg/ml。

Plasma concentrations of pentostatin following direct iv injection of 0.25 mg/kg daily for 4 or 5 days in a limited number of patients with advanced, refractory cancer ranged from approximately 3.2-9.7 ng/ml. Plasma concentrations appear to increase linearly with dose; in a study in patients with leukemia, plasma pentostatin concentrations determined 1 hour after administration of 0.25 or 1 mg/kg of the drug as a 30 min iv infusion averaged approximately 0.4 or 1.26 ug/ml, respectively.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

尽管没有记录平均或绝对血浆腺苷或脱氧腺苷浓度与喷托司汀治疗反应或毒性反应之间的明显相关性；然而，有限的数据表明，药物反应可能与淋巴细胞中脱氧腺苷三磷酸与腺苷三磷酸的比率有关。此外，据报道，血浆中脱氧腺苷的增加与红细胞和淋巴细胞中脱氧腺苷三磷酸的积累平行，并且毒性反应似乎与红细胞中脱氧腺苷三磷酸与腺苷三磷酸的比率有关。

No apparent correlation has been documented between mean or absolute plasma adenosine or deoxyadenosine concentrations and therapeutic or toxic responses to pentostatin; however, limited data suggest that there may be a correlation between response to the drug and the ratio of deoxyadenosine triphosphate to adenosine triphosphate in lymphoblasts. In addition, increases in plasma deoxyadenosine reportedly parallel the accumulation of deoxyadenosine triphosphate in erythrocytes and lymphoblasts, and there appears to be a correlation between toxicity and the ratio of deoxyadenosine triphosphate to adenosine triphosphate in erythrocytes.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

动物研究表明，喷托司汀迅速分布到所有身体组织，但药物在不同组织中的积累程度似乎因物种而异。在小鼠中进行腹腔注射后，药物在肾脏、肝脏和脾脏中的浓度最高。在狗中，静脉注射后喷托司汀的组织浓度与组织的腺苷脱氨酶活性成正比，以肺、脾、胰腺、心脏、肝脏和空肠中的浓度最高。据报道，喷托司汀通过一种与其他核苷类似的促进运输系统或简单扩散进入红细胞；尽管喷托司汀效果（例如，腺苷脱氨酶抑制）的时间过程在不同类型的细胞（例如，淋巴细胞、红细胞）之间有所不同，但药物从细胞中的流出尚未被表征。

Studies in animals indicate that pentostatin distributes rapidly to all body tissues, but the extent of drug accumulation in different tissues appears to vary among species. Following intraperitoneal injection in mice, the highest concentrations of the drug were found in the kidneys, liver, and spleen. In dogs, pentostatin tissue concentrations following iv administration were proportional to tissue adenosine deaminase activity, with the highest concentrations in the lungs, spleen, pancreas, heart, liver, and jejunum. Pentostatin reportedly enters erythrocytes via a facilitated transport system common to other nucleosides or by simple diffusion; efflux of the drug from cells has not been characterized, although the time course of pentostatin's effects (eg, adenosine deaminase inhibition) varies among different types of cells (eg, lymphocytes, erythrocytes).

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

动物和人类中的有限数据表明，喷托司汀进入脑脊液（CSF）的分布相对较差，CSF中的峰浓度平均大约为同期血浆浓度的10%。在一项针对6岁白血病患者的实验中，患者通过直接静脉注射连续三天每天接受0.25毫克/公斤的喷托司汀治疗，首次给药后4小时，通过酶抑制滴定分析法测得的血清和脑脊液（通过腰椎穿刺获得）中的喷托司汀浓度分别约为147和19纳克/毫升；在第三次给药后1小时，相应的血清和脑脊液浓度分别约为241和35纳克/毫升。

Limited data in animals and humans indicate that pentostatin distributes relatively poorly into CSF, with peak CSF concentrations averaging approximately 10% of concurrent plasma concentrations. In a 6 yr old leukemia patient receiving pentostatin 0.25 mg/kg daily for 3 successive days by direct iv injection, serum and CSF (via lumbar puncture) pentostatin concentrations 4 hr after the initial dose were approximately 147 and 19 ng/ml, respectively, using an enzyme-inhibition titration assay; one hour after the third dose, corresponding serum and CSF concentrations were approximately 241 and 35 ng/ml, respectively.

来源:Hazardous Substances Data Bank (HSDB)