Mechanism for the delayed elimination of SN-38 in cancer patients with severe renal failure and optimal treatment strategy

我们首次证明，尿毒症毒素如CMPF在临床相关浓度下抑制人肝细胞中的SN-38摄取。OATP 1B 1是人肝细胞中SN-38饱和摄取的主要贡献者。尿毒症血浆可下调SLCO 1B 1基因的表达。尿毒症毒素对OATP 1B 1介导的SN-38摄取的抑制和SLCO 1B 1基因表达的下调可能是导致重度肾功能不全患者中观察到的SN-38消除延迟的部分机制。

We have shown for the first time that uremic toxins such as CMPF inhibit SN-38 uptake in human hepatocytes at clinically relevant concentrations. OATP1B1 is a major contributor to the saturable uptake of SN-38 in human hepatocytes. The gene expression of SLCO1B1 was down-regulated by uremic plasma. The inhibition by uremic toxins of OATP1B1-mediated SN-38 uptake and the down-regulated SLCO1B1 gene expressions may be part of the mechanisms causing the delay of SN-38 elimination observed in patients with severe renal dysfunction.