伊立替康的临床药物动力学。
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伊立替康的临床药物动力学。
Pharmacokinet。1997年10月,33 (4):245 - 59。
- PubMed ID
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9342501 (在PubMed]
- 文摘
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本文综述了水溶性的临床药物动力学模拟的喜树碱,伊立替康(CPT-11或7-ethyl-10 - [4 - (1-piperidino) 1-piperidino] -carbonyloxy-camptoth eci n]。伊立替康,更有力的代谢物SN-38 (7 - ethyl-10-hydroxy-camptothecin),妨碍哺乳动物的DNA拓扑异构酶I和癌症细胞死亡似乎源于DNA链断裂引起的可分裂的复合物的形成。伊立替康治疗嗜中性白血球减少症的主要临床不良反应和腹泻。伊立替康显示活动白血病、淋巴瘤和以下癌症网站:colorectum,肺癌、卵巢、宫颈、胰腺、胃和乳房。通过静脉注射后伊立替康在100到350毫克/平方米,意味着最大伊立替康血浆浓度在1到10 mg / L的范围之内。等离子体浓度可以描述使用2 -或3-compartment模型意味着终端半衰期从5 - 27小时。在稳态(Vss)的体积分布范围从136到255 L / m2,全身间隙是8到21 L / h / m2。伊立替康是65%的血浆蛋白。血浆浓度时间曲线下面积的(AUC)伊立替康和SN-38增加比例接种剂量,尽管interpatient变化是很重要的。SN-38水平实现人类约100倍浓度低于相应的伊立替康,但这些浓度可能重要SN-38是100 - 1000倍更比母体化合物的细胞毒性。 SN-38 is 95% bound to plasma proteins. Maximum concentrations of SN-38 are reached about 1 hour after the beginning of a short intravenous infusion. SN-38 plasma decay follows closely that of the parent compound with an apparent terminal half-life ranging from 6 to 30 hours. In human plasma at equilibrium, the irinotecan lactone form accounts for 25 to 30% of the total and SN-38 lactone for 50 to 64%. Irinotecan is extensively metabolised in the liver. The bipiperidinocarbonylxy group of irinotecan is first removed by hydrolysis to yield the corresponding carboxylic acid and SN-38 by carboxyesterase. SN-38 can be converted into SN-38 glucuronide by hepatic UDP-glucuronyltransferase. Another recently identified metabolite is 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]-carbonyloxy-camptothecin (APC). This metabolite is a weak inhibitor of KB cell growth and a poor inducer of topoisomerase I DNA-cleavable complexes (100-fold less potent than SN-38). Numerous other unidentified metabolites have been detected in bile and urine. The mean 24-hour irinotecan urinary excretion represents 17 to 25% of the administered dose. Recovery of SN-38 and its glucuronide in urine is low and represents 1 to 3% of the irinotecan dose. Cumulative biliary excretion is 25% for irinotecan, 2% for SN-38 glucuronide and about 1% for SN-38. The pharmacokinetics of irinotecan and SN-38 are not influenced by prior exposure to the parent drug. The AUC of irinotecan and SN-38 correlate significantly with leuco-neutropenia and sometimes with the intensity of diarrhoea. Certain hepatic function parameters have been correlated negatively with irinotecan total body clearance. It was noted that most tumour responses were observed at the highest doses administered in phase I trials, which indicates a dose-response relationship with this drug. In the future, these pharmacokinetic-pharmacodynamic relationships will undoubtedly prove useful in minimising the toxicity and maximise the likelihood of tumour response in patients.