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

Authors

  • Xing Liu 10301 Stella Link Road, Houston, Texas 77025, USA.
  • Yang Wang 10301 Stella Link Road, Houston, Texas 77025, USA.
  • Zhisong Cao 10301 Stella Link Road, Houston, Texas 77025, USA.
  • Max Zhan Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 741 South Limestone, Lexington, KY, USA
  • Dana Vardeman 10301 Stella Link Road, Houston, Texas 77025, USA.
  • Beppino Giovanella 10301 Stella Link Road, Houston, Texas 77025, USA.

DOI:

https://doi.org/10.18433/J3B604

Abstract

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.

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Published

2013-05-08

How to Cite

Liu, X., Wang, Y., Cao, Z., Zhan, M., Vardeman, D., & Giovanella, B. (2013). Enhanced Lactone Stability of CZ48 in Blood Correlates to its Lack of Toxicity in Mice. Journal of Pharmacy & Pharmaceutical Sciences, 16(1), 115–124. https://doi.org/10.18433/J3B604

Issue

Section

Pharmaceutical Sciences; Review Articles