Abstract
Aim:
To investigate the pharmacokinetics and disposition of simmitecan (L-P) that was a water-soluble ester prodrug of chimmitecan (L-2-Z) with potent anti-tumor activities in different experimental animals, and to assess its drug-drug interaction potential.
Methods:
SD rats were injected with a single iv bolus doses of L-P (3.75, 7.5 and 15 mg/kg). The pharmacokinetics, tissue distribution, excretion and metabolism of L-P and its active metabolite L-2-Z were studied through quantitative measurements and metabolite profiling with LC/MS. The binding of L-P and L-2-Z to rat plasma proteins was examined using an ultrafiltration method. Systemic exposures of beagle dogs to L-P as well as drug distribution in tumors of the nude mice xenograft model of human hepatic cancer SMMC-7721 cells were also examined. The metabolism of L-P by liver mcirosomal carboxylesterase in vitro was investigated in different species. The effects of L-P and L-2-Z on cytochrome P450 enzymes were examined using commercial screening kits.
Results:
The in vivo biotransformation of L-P to L-2-Z showed a significant species difference, with a mean elimination half-life t1/2 of approximately 1.4 h in rats and 1.9 h in dogs. The systemic exposure levels of L-P and L-2-Z were increased in a dose-dependent manner. In rats, approximately 66% of L-P and 79% of L-2-Z were bound to plasma proteins. In rats and the nude mice bearing human hepatic cancers, most organ tissues had significantly higher concentrations of L-P than the corresponding plasma levels. In the tumor tissues, the L-P levels were comparable to those of plasma, whereas the L-2-Z levels were lower than the L-P levels. In rats, L-P was eliminated mainly via biliary excretion, but metabolism played an important role in elimination of the intact L-P. Finally, L-P and L-2-Z exerted moderate inhibition on the activity of CYP3A4 in vitro.
Conclusion:
L-P and L-2-Z have relatively short elimination half-lives and L-P is mainly eliminated via biliary excretion. The species difference in the conversion of L-P to L-2-Z and potential drug-drug interactions due to inhibition of CYP3A4 should be considered in further studies.
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Acknowledgements
This work was supported by the National Science & Technology Major Project of China “Key New Drug Creation and Manufacturing Program” (Grant no 2009ZX09304-002, 2009ZX09301-001 and 2009ZX09102-020), the National Natural Science Foundation of China (Grant no 30873120) and the Chinese National Natural Science Foundation for Distinguished Young Scholars (Grant no 30925044). The authors would like to thank Dr Jian DING and Dr Ze-hong MIAO from the Shanghai Institute of Materia Medica for their assistance.
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Hu, Zy., Li, Xx., Du, Ff. et al. Pharmacokinetic evaluation of the anticancer prodrug simmitecan in different experimental animals. Acta Pharmacol Sin 34, 1437–1448 (2013). https://doi.org/10.1038/aps.2013.74
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DOI: https://doi.org/10.1038/aps.2013.74
