Pharmacokinetic and pharmacodynamic evaluation of the topoisomerase inhibitor irinotecan in cancer patients
Pharmacokinetic and pharmacodynamic evaluation of the topoisomerase inhibitor irinotecan in cancer patients
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DOI：
10.1200/jco.1997.15.4.1502
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发表时间：
1997-04-01
影响因子：
45.3
通讯作者：
Ratain, MJ
中科院分区：
文献类型：
--
作者：
Gupta, E;Mick, R;Ratain, MJ
目的：我们对伊立替康（CPT-11）进行了药代动力学和药效学评价，并确定了种族和性别对CPT-11分布和毒性的影响。我们测试了对乙酰氨基酚（AAP）对表型SN-38 glucuronidation.Patients和Methods的疗效：40例患者接受了145 mg/m2的CPT-11 90分钟输注。定量血浆和尿液样本中的总CPT-11、SN-38和SN-38 G。结果：CPT-11的平均消除半衰期（t（1/2））为8.8小时，平均清除率（CL）为14.6 L/h/m2，稳态平均分布容积（Vd（ss））为136 L/m2。SN-38和SN-38 G的血浆利用度较低（相对于CPT-11为3%和10%），平均t（1/2）值分别为11.6和10.5小时。尿液回收率占剂量的15%。人种和性别对CPT-11、SN-38和SN-38 G的血浆利用度无影响。胆汁指数（BI）在预测剂量限制性肠道毒性中的适用性得到验证，与0至2级毒性患者相比，发生3级或4级毒性的患者的指数值显著更高（P = .001）。基于人种和性别，毒性的发生率和严重程度无差异。AAP是SN-38 glucuronidation.Conclusion的一个较差的预测因子：参数估计值的高度患者间变异性表明CPT-11的顺序代谢途径的药物遗传学变异或差异诱导或抑制，以及转运系统的变异性，低尿回收率表明大量的胆汁排泄，并支持肠道毒性和BI之间的显著相关性。黑人患者的以下风险未增加：毒性，SN-38结合的个体差异评估仍有待确定。(C)1997年，美国临床肿瘤学会。
Purpose: We conducted a pharmacokinetic and pharmacodynamic evaluation of irinotecan (CPT-11) and determined the effect of race and sex on disposition and toxicity of CPT-11. We tested the efficacy of acetaminophen (AAP) to phenotype SN-38 glucuronidation.Patients and Methods: Forty patients received a dose of 145 mg/m(2) of CPT-11 as a 90-minute infusion. Total CPT-11, SN-38, and SN-38G were quantitated in plasma and urine samples. Following administration of 1 g AAP, urinary concentrations of AAP and AAP-glucuronide (AAP-G) were assessed.Results: CPT-11 exhibited a mean elimination half-life (t(1/2)) of 8.8 hours, an average clearance (CL) of 14.6 L/h/m(2), and a mean volume of distribution at steady-state (Vd(ss)) of 136 L/m(2). SN-38 and SN-38G had low plasma availabilities (3% and 10% relative to CPT-11), with mean t(1/2) values of 11.6 and 10.5 hours, respectively. Urinary recovery accounted for 15% of the dose. Race and sex had no effect on the plasma availability of CPT-11, SN-38, and SN-38G. The applicability of biliary index (BI) in predicting dose-limiting intestinal toxicity was validated, patients who developed grade 3 or 4 toxicity had significantly higher index values compared with patients with grade 0 to 2 toxicity (P = .001). There was no difference in the incidence and severity of toxicity based on race and sex. AAP was a poor predictor of SN-38 glucuronidation.Conclusion: The high degree of interpatient variability in parameter estimates suggests pharmacogenetic variation or differential induction or inhibition of the sequential metabolic pathway of CPT-11, as well as variability in transport systems, The low urinary recovery indicates substantial biliary excretion and supports the significant correlation between intestinal toxicity and BI. Black patients are not at increased risk of: toxicity, An assessment of individual differences in SN-38 conjugation remains to be established. (C) 1997 by American Society of Clinical Oncology.