Okada Akira, Fukushima Keizo, Fujita Mai, Nakanishi Mana, Hamori Mami, Nishimura Asako, Shibata Nobuhito, Sugioka Nobuyuki
Department of Clinical Pharmacokinetics, Faculty of Pharmaceutical Sciences, Kobe Gakuin University.
Department of Biopharmaceutics, Faculty of Pharmaceutical Science, Doshisha Women's College of Liberal Arts.
Biol Pharm Bull. 2017;40(11):1948-1955. doi: 10.1248/bpb.b17-00499.
Cisplatin (CDDP)-induced acute kidney injury (AKI) is a major clinical concern. CDDP treatment is generally conducted with multiple cycles; the magnitude of the CDDP-induced AKI may be altered by these cycles. Moreover, sub-chronic kidney injury (sCKI) induced by repeated CDDP treatment is often associated with renal interstitial fibrosis, potentially leading to chronic kidney disease. Therefore, it is suggested that the management of not only AKI but also sCKI induced by CDDP in multiple cycles plays an important role in the outcome of CDDP-based chemotherapy. This study investigated the alteration in pharmacokinetics and toxicodynamics of CDDP that was repeatedly administered for three cycles in rats; a cycle consisted of CDDP (5.0 mg/kg, bolus injection) followed by a 21-d washout period. AKI and sCKI were evaluated by plasma creatinine concentration. In repeated multiple administration of CDDP, renal clearance was decreased and the amounts of accumulated Pt in kidneys increased by the cycle. AKI and sCKI were similarly exacerbated by the cycle, whereas the degree of AKI showed a large inter- and intra-individual variation in each cycle. However, the degree of sCKI constantly increased (creatinine increasing ratio in any cycle is about 150%), suggesting that the degree of sCKI in any given cycle was predictable by monitoring the initial creatinine baseline. In this study, therefore, it is suggested that the evaluation of sCKI by monitoring creatinine concentration at base is important for the estimation of CDDP-induced nephrotoxicity. These results may provide useful information for more effective and safe CDDP-based chemotherapy with evidence-based dose adjustment.
顺铂（CDDP）诱导的急性肾损伤（AKI）是一个主要的临床问题。CDDP治疗通常采用多个周期进行；这些周期可能会改变CDDP诱导的AKI的严重程度。此外，重复CDDP治疗诱导的亚慢性肾损伤（sCKI）常与肾间质纤维化相关，可能导致慢性肾脏病。因此，有人认为，对多周期CDDP诱导的AKI和sCKI的管理在基于CDDP的化疗结果中起着重要作用。本研究调查了在大鼠中重复给药三个周期的CDDP的药代动力学和毒代动力学变化；一个周期包括CDDP（5.0 mg/kg，静脉推注），随后是21天的洗脱期。通过血浆肌酐浓度评估AKI和sCKI。在重复多次给予CDDP时，肾脏清除率降低，肾脏中累积的Pt量随周期增加。AKI和sCKI在周期中同样加重，而每个周期中AKI的程度在个体间和个体内显示出较大差异。然而，sCKI的程度持续增加（任何周期中的肌酐增加率约为150%），这表明通过监测初始肌酐基线可以预测任何给定周期中sCKI的程度。因此，在本研究中，有人认为通过监测基线肌酐浓度评估sCKI对于估计CDDP诱导的肾毒性很重要。这些结果可能为基于CDDP的更有效和安全的化疗以及基于证据的剂量调整提供有用信息。
