Evaluation of the tissue distribution, excretion, and cytochrome P450 induction studies of a potential antitumor agent, TM-2, in animals using LC-MS/MS

被引:3
作者
Men, Lei [1 ,2 ]
Zhao, Yunli [2 ]
Lin, Hongxin [3 ]
Tang, Xing [2 ]
Yu, Zhiguo [2 ]
机构
[1] Dalian Nationalities Univ, Coll Life Sci, Dalian, Liaoning Provin, Peoples R China
[2] Shenyang Pharmaceut Univ, Sch Pharm, 103 Wenhua Rd, Shenyang 110016, Liaoning Provin, Peoples R China
[3] Dalian Weida Pharm Co Ltd, Dalian, Liaoning Provin, Peoples R China
关键词
A novel taxane derivative; cytochrome P450 enzyme; excretion; LC-MS/MS; tissue distribution; HUMAN LIVER-MICROSOMES; IN-VITRO METABOLISM; FELOTAXEL SHR110008; MASS-SPECTROMETRY; PROTEIN-BINDING; RATS; PHARMACOKINETICS; PACLITAXEL; DOCETAXEL; TAXANES;
D O I
10.1080/00498254.2016.1232446
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
1. TM-2 is a promising novel semi-synthetic taxane derivative with greater antitumor activity especially against resistant tumors and lower toxicity compared with docetaxel. Information on distribution and excretion of the pharmaceutical in animals, as well as biochemical information relevant to potential drug interactions should normally be evaluated prior to human clinical trials. 2. The present study investigated the tissue distribution and excretion of TM-2 in animals following intravenous administration for further advancement of the molecule. The potential inductive effect of TM-2 on cytochrome P450 iso-enzymes CYP 3A1 in rats was also evaluated. 3. The tissue distribution study in mice showed that TM-2 was rapidly dispersed in the various tissues and peak concentration levels were achieved within 0.083-1h. The highest concentration was detected in pancreas, followed by lung, kidney, spleen, heart and liver. TM-2 was mainly excreted in the feces via the bile (0.14% of the dose) and urinary excretion was minimal (0.007%). TM-2 increased CYP3A1 enzyme activities with time and dose dependence in rat liver microsome. 4. This important data serve as a useful resource to support further research of TM-2 and allow intelligent assessment of toxicology and in vivo activity testing performed in animals.
引用
收藏
页码:800 / 806
页数:7
相关论文
共 36 条
[1]  
[Anonymous], PROD DEV AN RUL GUID
[2]  
[Anonymous], 2001, GUID IND BIOAN METH
[3]   PRECLINICAL PHARMACOLOGY OF DOCETAXEL [J].
BISSERY, MC .
EUROPEAN JOURNAL OF CANCER, 1995, 31A :S1-S6
[4]   Assessement of the pharmacokinetics, tissue distribution and excretion studies of a novel antiplatelet agent S007-867, following administration to rats [J].
Chandasana, Hardik ;
Chhonker, Yashpal S. ;
Laxman, Tulsankar Sachin ;
Prasad, Yarra Durga ;
Kumar, Anil K. S. ;
Dikshit, Dinesh K. ;
Bhatta, Rabi S. .
DRUG TESTING AND ANALYSIS, 2016, 8 (07) :723-729
[5]  
China Food and Drug Administration, 2005, GUID PRECL PHARM CHE
[6]   Nonlinear accumulation in the brain of the new taxoid TXD258 following saturation of P-glycoprotein at the blood-brain barrier in mice and rats [J].
Cisternino, S ;
Bourasset, F ;
Archimbaud, Y ;
Sémiond, D ;
Sanderink, G ;
Scherrmann, JM .
BRITISH JOURNAL OF PHARMACOLOGY, 2003, 138 (07) :1367-1375
[7]   In-vitro metabolism of anti-cancer drugs, methods and applications: paclitaxel, docetaxel, tamoxifen and ifosfamide [J].
Crommentuyn, KML ;
Schellens, JHM ;
van den Berg, JD ;
Beijnen, JH .
CANCER TREATMENT REVIEWS, 1998, 24 (05) :345-366
[8]   In vitro assessment of cytochrome P450 inhibition and induction potential of felotaxel (SHR110008) [J].
Ding, Yi ;
Jia, YanYan ;
Lu, ChengTao ;
Liu, WenXing ;
Yang, Jing ;
Song, Ying ;
Zhu, YanRong ;
Yang, Lin ;
Ding, LiKun ;
Wen, AiDong .
BIOMEDICINE & PHARMACOTHERAPY, 2012, 66 (04) :318-321
[9]   Preclinical pharmacokinetic analysis of felotaxel (SHR110008), a novel derivative of docetaxel, in rats and its protein binding ability in vitro [J].
Ding, Yi ;
Liu, WenXing ;
Lu, ChengTao ;
Yang, Jing ;
Zhu, YanRong ;
Song, Ying ;
Ma, ZhongYing ;
Yang, Lin ;
Jia, YanYan ;
Wen, AiDong .
BIOMEDICINE & PHARMACOTHERAPY, 2012, 66 (02) :98-102
[10]   Strategies and molecular probes to investigate the role of cytochrome P450 in drug metabolism -: Focus on in vitro studies [J].
Donato, MT ;
Castell, JV .
CLINICAL PHARMACOKINETICS, 2003, 42 (02) :153-178