Pharmacokinetics, tissue distribution, and metabolism of novel DNA topoisomerase I inhibitor yuanhuacine in rabbit

Abstract

1. A liquid chromatography/tandem mass spectrometry method was developed and validated for the quantitative determination of yuanhuacine (YHC), a daphne diterpene ortho-ester anticancer agent, and identification of its metabolites.

2. Pharmacokinetic behaviour, tissue distribution, and metabolism were investigated in rabbit. YHC plasma data best fitted to a two-compartment model and were characterized by an elimination half-life t_1/2(β) of 11.1 h following intravenous administration. Tissue distribution studies did not identify any tissues having a high affinity for YHC.

3. The main metabolites are proposed to be M392I, M392II, and M390, resulting from the ortho-ester group and aromatic ester bond being cleaved off simultaneously during Phase I metabolism.

4. This investigation contributes to an understanding of the metabolism of daphne diterpene ortho-esters.

Keywords::

• Yuanhuacine
• pharmacokinetics
• metabolism
• DNA topoisomerase I inhibitor
• anti-cancer agent

Acknowledgments

The authors would like to express thanks to Dr Jianzhang Zhao for the valued help in the preparation of the manuscript.

Declaration of interest: The authors report no conflicts of interest.