483P - Change in Plasma Protein Binding of Sn-38, an Active Metabolite of Irinotecan, in Cancer Patients with Severe Renal Failure (Srf)

Abstract

ABSTRACT Aim: Our previous clinical study revealed that total plasma concentration of SN-38 was higher in cancer patients with SRF than those with normal kidney (NK), although SN-38 is mainly eliminated in the liver. Because SN-38 can bind to plasma protein, we hypothesized the possible increase in unbound fraction of SN-38 and area under the unbound plasma concentration-time curve (AUCu) caused by inhibition of plasma protein binding by uremic toxin(s) in patients with SRF. Methods: Total and unbound plasma concentrations of SN-38 in the cancer patients treated with 100 mg/m2 irinotecan alone were examined at 1 h after the end of irinotecan infusion to obtain unbound fraction of SN-38. Ex vivo analyses for SN-38 protein binding were performed with plasma samples obtained from 4 respective groups of patients (10-12 for each group) categorized by their renal function, estimated glomerular filtration (eGFR) 60 mL/min. The inhibition by 22 uremic toxins known to bind to plasma protein of SN-38 protein binding was also examined. Results: Unbound fraction of SN-38 in 3 cancer patients with SRF (0.023 ± 0.0060) was significantly higher than that in 5 of those with NK (0.0089 ± 0.0043) (P = 0.0339). AUCu in patients with SRF and those with NK were 0.030 ± 0.015 and 0.0069 ± 0.0043 µM·h, respectively (P = 0.0253). Ex vivo experiments revealed that unbound fractions of SN-38 was inversely correlated with eGFR (Spearman's rank correlation coefficient, -0.5207; P = 0.0003). The unbound fractions in patients with eGFR Conclusions: Unbound concentrations of SN-38 were higher in patients with SRF than those with NK. The inhibition of SN-38 protein binding by CMPF is a possible mechanism. Disclosure: All authors have declared no conflicts of interest.