Details

Autor(en) / Beteiligte

• Hu, Zhe-yi
• Li, Xiu-xue
• Du, Fei-fei
• Yang, Jun-ling
• Niu, Wei
• Xu, Fang
• Wang, Feng-qing
• Li, Chuan
• Sun, Yan

Titel

Pharmacokinetic evaluation of the anticancer prodrug Simmitecan in different experimental animals

Ist Teil von

• Acta pharmacologica Sinica, 2013-11, Vol.34 (11), p.1437-1448

Ort / Verlag

London: Nature Publishing Group UK

Erscheinungsjahr

2013

Quelle

MEDLINE

Beschreibungen/Notizen

• 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 mp=/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 tl/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.