TAMOXIFEN ANTI-ESTROGENS - A COMPARISON OF THE ACTIVITY, PHARMACOKINETICS, AND METABOLIC-ACTIVATION OF THE CIS-ISOMER AND TRANS-ISOMER OF TAMOXIFEN
TAMOXIFEN ANTI-ESTROGENS - A COMPARISON OF THE ACTIVITY, PHARMACOKINETICS, AND METABOLIC-ACTIVATION OF THE CIS-ISOMER AND TRANS-ISOMER OF TAMOXIFEN
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DOI：
10.1016/0022-4731(82)90137-6
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发表时间：
1982-01-01
影响因子：
4.1
通讯作者：
KATZENELLENBOGEN, BS
中科院分区：
文献类型：
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作者：
ROBERTSON, DW;KATZENELLENBOGEN, JA;KATZENELLENBOGEN, BS
在大鼠子宫中，顺式他莫昔芬（ci - 47,699,1 -[4-（2-二甲氨基乙氧基）苯基]-1,2-二苯基丁-1(E)-烯）是一种完全雌激素激动剂，而反式他莫昔芬（ci - 46,474,1 -[4-（2-二甲氨基乙氧基）苯基]-1,2-二苯基丁-1-(Z)-烯）是一种部分拮抗剂-部分激动剂。比较了三苯氧胺异构体在大鼠体内的生物活性，并利用这些异构体以3h标记的形式进行了代谢和药效学研究。在未成熟大鼠中，就子宫重量刺激而言，反式他莫昔芬是部分激动剂-部分拮抗剂，而顺式他莫昔芬是纯激动剂；两种异构体对子宫过氧化物酶的刺激作用都很小，而只有反式他莫昔芬能够拮抗雌二醇对过氧化物酶的刺激作用。大鼠体内给予[3H]-反式他莫昔芬后，反式羟他莫昔芬在子宫核部分逐渐积累，并且有更多的极性代谢物。另一方面，对于[3H]-顺式他莫昔芬，这些代谢物在子宫内没有积累：在核部分，有一种代谢物的极性略低于顺式羟基他莫昔芬，在细胞质中，有一种代谢物的极性略高于顺式他莫昔芬（但与核代谢物不同）。没有证据表明他莫昔芬或羟他莫昔芬的异构体有异构化。在与大鼠肝微粒体的体外培养中，[3H]-反式他莫昔芬和[3H]-顺式他莫昔芬均发生羟基化和较小程度的去甲基化。因此，与顺式羟他莫昔芬（5%）相比，反式羟他莫昔芬在子宫中的选择性积累似乎是由于其对雌激素受体的亲和力更强（285%，雌二醇= 100%）。在使用反式或顺式他莫昔芬治疗后，子宫内积累的不同代谢物可能解释了它们不同的激动-拮抗剂特性。
In the rat uterus, cis-tamoxifen (ICI-47,699, 1-[4-(2-dimethylaminoethoxy)phenyl]-1,2-diphenylbut-1(E)-ene) is a full estrogen agonist, while trans-tamoxifen (ICI-46,474, 1-[4-(2-dimethylaminoethoxy)phenyl]-1,2-diphenylbut-1-(Z)-ene) is a partial antagonist-partial agonist. The bioactivity of the tamoxifen isomers in the rat were compared and utilizing these isomers in 3H-labeled form, their metabolism and pharmacodynamics were examined. In immature rats, trans-tamoxifen is a partial agonist-partial antagnoist in terms of uterine weight stimulation, while cis-tamoxifen is a pure agonist; both isomers give little stimulation of uterine peroxidase, while only trans-tamoxifen is able to antagonize peroxidase stimulation by estradiol. After administration of [3H]-trans-tamoxifen to rats in vivo, there is a progressive accumulation of trans-hydroxytamoxifen and a yet more polar metabolite in the nuclear fraction of the uterus. With [3H]-cis-tamoxifen, on the other hand, there is no accumulation of these metabolites in the uterus: in the nuclear fraction, there is a metabolite that is slightly less polar than cis-hydroxytamoxifen, and in the cytosol, a metabolite slightly more polar than cis-tamoxifen (but different from the nuclear metabolite). There is no evidence for isomerization of the isomers of tamoxifen or hydroxytamoxifen. In in vitro incubations with rat liver microsomes, both [3H]-trans-tamoxifen and [3H]-cis-tamoxifen undergo hydroxylation and to a lesser extent demethylation. Thus, the selective accumulation of trans-hydroxytamoxifen in the uterus appears to result from its greater affinity for the estrogen receptor (285%, vs. estradiol = 100%) relative to that of cis-hydroxytamoxifen (5%). The different metabolites that accumulate in the uterus following treatment with trans or cis tamoxifen may account for their different agonist-antagonist character.