Pharmacokinetics and Enterohepatic Recycling of CZ48, a Lactone-Stabilized Camptothecin: Effects of Nanosuspension Formulation

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2017-08

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Abstract

CZ48, a lactone-stabilized camptothecin (CPT), is a topoisomerase 1 enzyme inhibitor. Its strong potential as an anticancer agent has been demonstrated against various types of human tumors with a lack of toxicity in human tumor-xenografted mice. In addition, previous preclinical pharmacokinetic (PK) studies implied potential enterohepatic recycling of CZ48 and CPT responsible for their sustained concentrations in plasma for 6 hr after an oral dose of CZ48 in co-solvent formulation. The prolonged exposure of a drug by enterohepatic recycling may significantly alter drug PK and pharmacological effects, and cause unpredictable toxicity by multiple dosing. Hence, it is critical to characterize the hepatic metabolism, biliary excretion and enterohepatic recycling using preclinical models in early stages of drug discovery and development. Moreover, nanosuspension (NS) of CZ48 has been formulated in our laboratory to overcome its poor water solubility. Thus, the overall objective of this project was to evaluate the impacts of NS on biodistributions of CZ48 and CPT in human tumor-xenografted mice, and biliary excretions and enterohepatic recycling in rats. Different biodistribution patterns of CZ48 were observed between co-solvent (CoS) and NS groups in tumor-xenografted mice; however, the pattern of CPT was similar between CoS and NS groups. The highest exposure of CPT was in the liver and the lowest was in the brain. The extent of CPT exposure in tumor was comparable with those in kidney, spleen, and lung. Half-lives of CZ48 and CPT were 1.5 – 3.6 times increased in all tested organs and tumor. The prolonged exposure of CPT may offer a merit of NS for its antitumor activity as a topoisomerase 1 inhibitor of cell-cycle S-phase specific activity. In enterohepatic recycling study, biliary secretions of CZ48 and CPT were confirmed mainly by their parent forms not conjugates. After an intravenous (IV) dose of CZ48-CoS, the percentages of dose recovered in bile were 0.19 % and 3.05 % for CZ48 and CPT, respectively, indicating more favorable biliary secretion of CPT than CZ48. NS did not significantly increase biliary excretions of CZ48 and CPT, with comparable AUC0-12h ratios of CZ48 (or CPT) in bile to plasma (B/P) after an oral dose between CZ48-NS and CZ48-CoS. Enterohepatic recycling of CZ48 and CPT was minor, since their plasma concentration-time profiles and biliary secretions exhibited similar trends with or without interrupting the recycling. Our PK model adequately described plasma concentrations of CZ48 and CPT and biliary excretion of CPT when adopting compartments for enterohepatic recycling. In conclusion, this is the first report evaluating biliary excretions of CZ48 and CPT, and characterizing their enterohepatic recycling by employing in vitro, in vivo, and PK modeling approaches. Our findings on the metabolisms, biodistributions, biliary excretions, and enterohepatic recycling of CZ48 and CPT are significant, and has enabled us to rationalize the clinical PK of CZ48 and CPT in the currently ongoing phase 1 clinical trials.

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Keywords

CZ48, Camptothecin, Nanosuspensions, Biodistribution, Biliary Excretion, Enterohepatic Recycling

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