Department of Clinical Pharmacy, Faculty of Pharmaceutical Science, Kyoto Pharmaceutical University, 5 Nakauchi-cho, Misasagi, Yamashina-ku, Kyoto, 607-8414, Japan.
Department of Pharmacy Service, Shirasagi Hospital, Osaka, 546-0002, Japan.
Cancer Chemother Pharmacol. 2018 Jun;81(6):1121-1128. doi: 10.1007/s00280-018-3583-y. Epub 2018 Apr 24.
Pharmacokinetics and pharmacodynamics of irinotecan have been reported to be altered in cancer patients with end-stage kidney disease (ESKD). Carboxylesterase (CES) has an important role in metabolism of irinotecan to its active metabolite, SN-38, in human liver. The purpose of the present study was to investigate whether CES activity was altered in ESKD patients.
The present study investigated the effects of uremic serum, uremic toxins, and fatty acids on the hydrolysis of irinotecan and a typical CES substrate, p-nitrophenyl acetate (PNPA), in human liver microsomes. Normal and uremic serum samples were deproteinized by treatment with methanol were used in the present study.
The present study showed that both normal and uremic serum significantly inhibited CES-mediated metabolism of both irinotecan and PNPA. The inhibition by uremic serum was weaker than that by normal serum, suggesting that CES activity may be higher in ESKD patients. Although four uremic toxins did not affect PNPA metabolism, arachidonic acid inhibited it. There was no difference in inhibitory effect of PNPA metabolism between both mixtures of seven fatty acids used at concentrations equivalent to those present in 10% normal or uremic serum. Interestingly, those mixtures had a more pronounced effect than either 10% normal or uremic serum.
The present study showed that the inhibition of CES activity by uremic serum was weaker than that by normal serum, suggesting that an increase in maximum plasma concentration of SN-38 in cancer patients with ESKD can be attributed to an accelerated CES-mediated irinotecan hydrolysis.
已有报道称，患有终末期肾病（ESKD）的癌症患者的伊立替康药代动力学和药效学发生了改变。羧酸酯酶（CES）在伊立替康代谢为其活性代谢物 SN-38 的过程中，在人肝中起着重要作用。本研究旨在探讨 CES 活性是否在 ESKD 患者中发生改变。
本研究调查了尿毒症血清、尿毒症毒素和脂肪酸对人肝微粒体中伊立替康和典型 CES 底物对硝基苯乙酸酯（PNPA）水解的影响。本研究使用了正常和尿毒症血清样本，用甲醇处理进行脱蛋白。
本研究表明，正常和尿毒症血清均显著抑制 CES 介导的伊立替康和 PNPA 的代谢。尿毒症血清的抑制作用弱于正常血清，提示 ESKD 患者的 CES 活性可能更高。虽然四种尿毒症毒素不影响 PNPA 代谢，但花生四烯酸抑制了它。两种混合物在抑制 PNPA 代谢方面没有差异，这两种混合物在浓度相当于 10%正常或尿毒症血清中存在的浓度时使用的七种脂肪酸混合物。有趣的是，这些混合物的效果比 10%正常或尿毒症血清更显著。
本研究表明，尿毒症血清对 CES 活性的抑制作用弱于正常血清，提示 ESKD 癌症患者的 SN-38 最大血浆浓度增加可能归因于 CES 介导的伊立替康水解加速。
