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01-10-2007 | Original Article

Tetrandrine achieved plasma concentrations capable of reversing MDR in vitro and had no apparent effect on doxorubicin pharmacokinetics in mice

Authors: Chun-Ling Dai, Hui-Yu Xiong, Li-Fen Tang, Xu Zhang, Yong-Ju Liang, Mu-Sheng Zeng, Li-Ming Chen, Xiao-Hong Wang, Li-Wu Fu

Published in: Cancer Chemotherapy and Pharmacology | Issue 5/2007

Abstract

Purpose

Tetrandrine (Tet), a multidrug resistant (MDR) modulator, was a potential candidate for use in cancer therapy and exhibited potent biological activity in vitro and in vivo when combined with anticancer agents such as doxorubicin, paclitaxel. Our aims were to determine whether serum concentration of Tet, which was capable of blocking P-gp in vitro, could be safely achieved in mice and whether Tet induced pharmacokinetic alterations in serum doxorubicin disposition in mice.

Methods

Tet of 30 mg/kg dose used to reverse MDR was administrated intraperitoneally in mice. Plasma Tet and serum doxorubicin concentration were analyzed by HPLC. CYP 3A4 activity was examined by HPLC with the substrate of nifedipine.

Results

More than 1 μmol/L of Tet could at least tenfold reverse MDR in vitro. The plasma peak concentration of Tet was about 2 μmol/L and not less than 1 μmol/L until 18 h following Tet administration (i.p.) at 30 mg/kg. These suggested that the concentrations of Tet that were sufficient to inhibit P-gp might be achieved in mice receiving 30 mg/kg of Tet. Importantly, no significant difference was demonstrated between the doxorubicin pharmacokinetic parameters obtained in mice received doxorubicin only and doxorubicin plus Tet. This implied that Tet of 30 mg/kg did not alter the profiles of pharmacokinetics of doxorubicin including the clearance and AUC of doxorubicin. Furthermore, Tet did not significantly affect on CYP 3A4 activity in human liver microsomes until more than 25 μmol/L.

Conclusions

Tet at the tested dose of combination treatment could achieve plasma concentrations that reversed MDR in experimental models and it had no apparent effect on doxorubicin pharmacokinetics in mice and CYP 3A4 activity in human liver microsomes.

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Title: Tetrandrine achieved plasma concentrations capable of reversing MDR in vitro and had no apparent effect on doxorubicin pharmacokinetics in mice
Authors: Chun-Ling Dai
Hui-Yu Xiong
Li-Fen Tang
Xu Zhang
Yong-Ju Liang
Mu-Sheng Zeng
Li-Ming Chen
Xiao-Hong Wang
Li-Wu Fu
Publication date: 01-10-2007
Publisher: Springer-Verlag
Published in: Cancer Chemotherapy and Pharmacology / Issue 5/2007
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-007-0420-0

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