Pharmacokinetics of endoxifen and tamoxifen in female mice: implications for comparative in vivo activity studies.
Pharmacokinetics of endoxifen and tamoxifen in female mice: implications for comparative in vivo activity studies.
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DOI：
10.1007/s00280-014-2605-7
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发表时间：
2014-12
影响因子：
3
通讯作者：
Ames, Matthew M.
中科院分区：
文献类型：
--
作者：
Reid, Joel M.;Goetz, Matthew P.;Buhrow, Sarah A.;Walden, Chad;Safgren, Stephanie L.;Kuffel, Mary J.;Reinicke, Kathryn E.;Suman, Vera;Haluska, Paul;Hou, Xiaonan;Ames, Matthew M.
CYP2D6代谢降低和低Z-endoxifen （ENDX）浓度可能会增加他莫昔芬（TAM）治疗女性乳腺癌复发的风险。TAM和ENDX的小鼠药代动力学差异以及给药途径对两种药物血药浓度的影响尚不清楚。对TAM和ENDX在雌性小鼠体内的药动学进行了研究。用于皮下[s.c。]和口服TAM(4、10和20 mg/kg)， TAM AUC呈线性增加，但活性代谢物[ENDX和4-羟他莫昔芬（4HT）]的浓度仍然很低。口服TAM (20 mg)， 4HT浓度比TAM治疗的人高10倍（25 ng/ml）。口服（10-200 mg/kg）和s.c (2.5-25 mg/kg) ENDX·HCl均导致AUC的增加大于剂量比例，其ENDX浓度比同等剂量的TAM高8倍。给药25或100 mg/kg ENDX·HCl 5天后，ENDX在血浆中积累，分别超过0.1 μM和1.0 μM的目标浓度2 - 4倍。在小鼠模型中，与TAM相比，口服ENDX产生更高的ENDX浓度。在接受s.c TAM的小鼠中观察到的低4HT和ENDX浓度反映了TAM在CYP2D6代谢受损的人体内的药代动力学。这些数据支持了ENDX作为er阳性乳腺癌内分泌治疗新药物的持续发展。
Reduced CYP2D6 metabolism and low Z-endoxifen (ENDX) concentrations may increase the risk of breast cancer recurrence in tamoxifen (TAM)-treated women. Little is known regarding the differences between TAM and ENDX murine pharmacokinetics or the effect of administration route on plasma concentrations of each drug. The pharmacokinetics of TAM and ENDX were characterized in female mice. For subcutaneous [s.c.] and oral TAM (4, 10 and 20 mg/kg), TAM AUC increased in a linear manner, but concentrations of the active metabolites [ENDX and 4-hydroxytamoxifen (4HT)] remained low. For oral TAM (20 mg), 4HT concentrations were tenfold greater (>25 ng/ml) than achievable in TAM-treated humans. Both oral (10–200 mg/kg) and s.c. (2.5–25 mg/kg) ENDX·HCl resulted in a greater than dose-proportional increase in AUC, with eightfold greater ENDX concentrations than an equivalent TAM dose. ENDX accumulated in plasma after 5-day dosing of 25 or 100 mg/kg ENDX·HCl and exceeded target concentrations of 0.1 and 1.0 μM, respectively, by twofold to fourfold. In murine models, oral ENDX yields substantially higher ENDX concentrations, compared to TAM. The low 4HT and ENDX concentrations observed in mice receiving s.c. TAM mirror the TAM pharmacokinetics in humans with impaired CYP2D6 metabolism. These data support the ongoing development of ENDX as a novel agent for the endocrine treatment of ER-positive breast cancer.
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影响因子：
10.3
作者：
Rae, James M.;Drury, Suzy;Dowsett, Mitch
通讯作者：
Dowsett, Mitch
影响因子：
10.3
作者：
Regan, Meredith M.;Leyland-Jones, Brian;Viale, Giuseppe
通讯作者：
Viale, Giuseppe
DOI：
10.1016/0022-4731(82)90137-6
发表时间：
1982-01-01
影响因子：
4.1
作者：
ROBERTSON, DW;KATZENELLENBOGEN, JA;KATZENELLENBOGEN, BS
通讯作者：
KATZENELLENBOGEN, BS
影响因子：
2.1
作者：
Bekaii-Saab, TS;Perloff, MD;von Moltke, LL
通讯作者：
von Moltke, LL
影响因子：
3.8
作者：
Karle, Jennifer;Bolbrinker, Juliane;Regierer, Anne C.
通讯作者：
Regierer, Anne C.