Abstract 3886: Impact of nanosuspension of CZ48, a lactone stabilized camptothecin, on the biliary excretion and enterohepatic recycling of its active moiety, camptothecin

Abstract

Abstract The biliary excretions of CZ48, a lactone-stabilized camptothecin (CPT), and CPT were evaluated in bile duct-cannulated SD rats after a single oral administration of CZ48 in two different types of formulations, co-solvent solution (CoS, control, in the mixture of DMSO, PEG 400, and EtOH (2:2:1, v/v/v) at 10 mg/ml) and nanosuspension (NS with stabilizers of TW 80 and F-108, sustained release of CZ48). Enterohepatic recycling was further characterized by collecting bile intermittently or continuously to modulate the recycling system in the rats. The results demonstrated that CZ48 and CPT were secreted into the bile as their parent forms with the dominant secretion of CPT as compared to CZ48. The AUCs0-12h of CPT in bile were 213.45 ± 232.09 and 250.40 ± 134.83 ng/ml*h/[mg/kg] in CoS and NS groups, respectively, which were 18.39 and 34.16 times higher than those of CZ48 (11.61 ± 7.99 ng/ml*h/[mg/kg] in the CoS group and 7.33 ± 2.22 ng/ml*h/[mg/kg] in the NS group). On the contrary, the AUCs0-12h of CZ48 in plasma were 6.10 and 6.80 times higher than those of CPT in CoS and NS groups, respectively. There was no significant impact of NS on the plasma AUCs0-12h and biliary excretions of CZ48 and CPT. Their concentrations in plasma and biliary excretions were sustained for 8 or 12 h post oral dose. Moreover, a pharmacokinetic co-model for CZ48 and CPT in plasma and bile was developed to characterize the biliary secretion and saturable process of enterohepatic recycling of CZ48 and CPT in rats. Citation Format: Diana S-L Chow, Yu Jin Kim, Dong Dong, Xiaohui Li. Impact of nanosuspension of CZ48, a lactone stabilized camptothecin, on the biliary excretion and enterohepatic recycling of its active moiety, camptothecin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3886.