Enhanced Lactone Stability of CZ48 in Blood Correlates to its Lack of Toxicity in Mice

Xing Liu1, Yang Wang1, Zhisong Cao1, Max Zhan2, Dana Vardeman1, Beppino Giovanella1

110301 Stella Link Road, Houston, Texas 77025, USA.
2Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 741 South Limestone, Lexington, KY, USA


Purpose. The aim of this study was to correlate the relationship between the pharmacokinetic behaviors and the toxicity of a new investigational anticancer agent CZ48, a C20-propionate ester of camptothecin (CPT) in mice. Methods. In this study, the safety and pharmacokinetics of oral doses of CZ48 were compared with the oral doses of CPT. Mice were administered orally one of three single doses of CZ48 (50, 200 and 1000 mg/kg) and two single doses of CPT (1.5 mg/kg and 6.0 mg/kg). Blood samples were collected from all mice at the defined time points after drug administration for assessment of plasma CZ48 and CPT concentrations. Results. The study showed that CZ48 was very stable in mouse blood and the majority of this agent stayed intact as the lactone form when in circulation, with only a small fraction of the CZ48 molecules metabolized into CPT. The concentration of the metabolite CPT measured in the mouse blood was only 3% of the concentration found for the maximum tolerated dose (6.0 mg/kg) of plain CPT. The stability difference between CZ48 and CPT in blood was structurally explained by the geometry of these two molecules. Conclusion. The lack of toxicity of CZ48 at effective doses in mice is attributed to its enhanced stability in their blood.

This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

J Pharm Pharm Sci, 16 (1): 115-124, 2013

Full Text: