Tetrandrine achieved plasma concentrations capable of reversing MDR in vitro and had no apparent effect on doxorubicin pharmacokinetics in mice.
OBJECTIVE
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 micromol/L of Tet could at least tenfold reverse MDR in vitro. The plasma peak concentration of Tet was about 2 micromol/L and not less than 1 micromol/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 micromol/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.
Dai
Chun-Ling
CL
State Key Laboratory of Oncology in Southern China, Cancer Center, Sun Yat-Sen University, Guangzhou 510060, China.
Xiong
Hui-Yu
HY
Tang
Li-Fen
LF
Zhang
Xu
X
Liang
Yong-Ju
YJ
Zeng
Mu-Sheng
MS
Chen
Li-Ming
LM
Wang
Xiao-Hong
XH
Fu
Li-Wu
LW
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000032:analysis; D000470:Alkaloids / Q000097:blood* / Q000494:pharmacology; D000818:Animals; D044182:Benzylisoquinolines / Q000097:blood* / Q000494:pharmacology; D045744:Cell Line, Tumor; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000032:analysis*; D004317:Doxorubicin / Q000097:blood* / Q000493:pharmacokinetics; D019008:Drug Resistance, Neoplasm; D006801:Humans; D051379:Mice; D008862:Microsomes, Liver / Q000737:chemistry; D014750:Vincristine / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000470:Alkaloids; D044182:Benzylisoquinolines; C009438:tetrandrine; D014750:Vincristine; D004317:Doxorubicin; D003577:Cytochrome P-450 Enzyme System; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human