Kisanga E R, Gjerde J, Schjøtt J, Mellgren G, Lien E A
The Hormone Laboratory, Department of Clinical Biochemistry, Haukeland University Hospital, University of Bergen, Norway.
J Steroid Biochem Mol Biol. 2003 Feb;84(2-3):361-7. doi: 10.1016/s0960-0760(03)00051-7.
We investigated the kinetics of tamoxifen (tam) in immunodeficient mice and rats after oral treatment and compared drug and metabolite profile in nude rat serum and tissues after oral and subcutaneous (s.c.) routes of administration. The serum levels were compared to those observed in man. After oral dosing in mice, tam and the potent metabolite 4-hydroxytamoxifen (4-hydroxytam), were detectable in liver and lung tissue, but not in serum. The levels of 4-hydroxytam in these tissues were significantly higher than those of tam, a profile opposite to that observed in rat and man. In rats and man, the 4-hydroxytam/tam serum concentration ratios were 0.16 and 0.02, respectively. Compared to oral route, the s.c. pellets yielded only trace amounts of the demethylated derivatives of tam in rats. Thus, the kinetics of tam observed in the present study suggest that the nude rat may represent a preferable animal model in studying the pharmacokinetics of tam and that, the oral route yielded higher serum and tissue levels of tam and metabolites than equivalent s.c. pellet implants.
我们研究了口服给药后他莫昔芬（tam）在免疫缺陷小鼠和大鼠体内的动力学，并比较了口服和皮下（s.c.）给药途径后裸鼠血清和组织中的药物及代谢物谱。将血清水平与在人体中观察到的水平进行比较。小鼠口服给药后，在肝脏和肺组织中可检测到tam和强效代谢物4-羟基他莫昔芬（4-羟基tam），但在血清中未检测到。这些组织中4-羟基tam的水平显著高于tam，这一情况与在大鼠和人体中观察到的相反。在大鼠和人体中，4-羟基tam/tam血清浓度比分别为0.16和0.02。与口服途径相比，皮下植入丸剂在大鼠体内仅产生痕量的tam去甲基化衍生物。因此，本研究中观察到的tam动力学表明，裸鼠可能是研究tam药代动力学的更优动物模型，并且口服途径比同等剂量的皮下植入丸剂产生更高的血清和组织中tam及代谢物水平。
