Increased Plasma Concentrations of Unbound SN-38, the Active Metabolite of Irinotecan, in Cancer Patients with Severe Renal Failure
Increased Plasma Concentrations of Unbound SN-38, the Active Metabolite of Irinotecan, in Cancer Patients with Severe Renal Failure
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DOI：
10.1007/s11095-015-1785-0
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发表时间：
2016-02-01
影响因子：
3.7
通讯作者：
Kato, Yukio
中科院分区：
文献类型：
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作者：
Fujita, Ken-ichi;Masuo, Yusuke;Kato, Yukio
在严重肾功能衰竭（SRF）的癌症患者中观察到活性伊立替康代谢物SN-38的延迟血浆浓度谱，尽管SN-38主要通过肝脏消除。在这里，我们检测了这些患者未结合的SN-38的血浆浓度。超滤检测血浆游离浓度。建立伊立替康和SN-38的生理药代动力学（PBPK）模型，定量评估延迟SN-38消除的主要机制。SRF患者SN-38的血浆未结合浓度-时间曲线下面积（AUC(u)）是正常肾脏患者的4.38倍。在这些患者中，SN-38的未结合部分也高出2.6倍，部分原因是SN-38蛋白结合被尿毒症毒素3-羧基-4-甲基-5-丙基-2-呋喃丙酸（CMPF）取代。这一结果得到了SN-38未结合部分与血浆CMPF浓度相关的支持，而CMPF浓度与肾功能呈负相关。PBPK模型显示，SN-38流入肝细胞的量大大减少，SRF患者约三分之一的伊立替康剂量可产生与正常肾脏患者相似的未结合的SN-38浓度分布。SRF癌患者SN-38的AUC(u)远大于正常肾脏患者，主要原因是肝脏对SN-38的摄取减少。
Delayed plasma concentration profiles of the active irinotecan metabolite SN-38 were observed in cancer patients with severe renal failure (SRF), even though SN-38 is eliminated mainly via the liver. Here, we examined the plasma concentrations of unbound SN-38 in such patients.Plasma unbound concentrations were examined by ultrafiltration. Physiologically-based pharmacokinetic (PBPK) models of irinotecan and SN-38 were established to quantitatively assess the principal mechanism for delayed SN-38 elimination.The area under the plasma unbound concentration-time curve (AUC(u)) of SN-38 in SRF patients was 4.38-fold higher than that in normal kidney patients. The unbound fraction of SN-38 was also 2.6-fold higher in such patients, partly because SN-38 protein binding was displaced by the uremic toxin 3-carboxy-4-methyl-5-propyl-2-furanpropionate (CMPF). This result was supported by correlation of the unbound fraction of SN-38 with the plasma CMPF concentration, which negatively correlated with renal function. PBPK modeling indicated substantially reduced influx of SN-38 into hepatocytes and approximately one-third irinotecan dose for SRF patients to produce an unbound concentration profile of SN-38 similar to normal kidney patients.The AUC(u) of SN-38 in SRF cancer patients is much greater than that of normal kidney patients primarily because of the reduced hepatic uptake of SN-38.