Ruenitz P C, Bai X
College of Pharmacy, University of Georgia, Athens 30602-2352, USA.
Drug Metab Dispos. 1995 Sep;23(9):993-8.
The nonsteroidal antiestrogen tamoxifen (TAM) is subject to extensive biotransformation in humans and laboratory animals. In particular, the dimethylamino group of TAM undergoes N-demethylation and formal replacement with a hydroxyl group, affording major metabolites TAM amine and TAM alcohol, respectively. In the present study in ovariectomized rats, TAM was eliminated in part as metabolites arising from conversion of its basic side chain to an oxyacetic acid moiety. Thus, TAM acid (TA) was characterized spectrally from the urine of rats after intraperitoneal administration of TAM. TA was not detected in fecal extracts. In contrast, a second metabolite, 4-hydroxy TA (4HTA), was detected and characterized only from fecal extracts, indicative of a qualitative difference in routes of elimination for TA and 4HTA. Studies with rat liver fractions suggested TAM alcohol to be an intermediate metabolite in the conversion of TAM to TA and 4HTA. In liver microsomal fraction, TAM alcohol was converted to a novel metabolite, TAM aldehyde, which was isolated and characterized as its semicarbazone derivative. Coenzyme requirements for formation of this (derivative) metabolite, as well as for conversion of TA to 4HTA, indicated these transformations to be catalyzed by cytochromes P450. TAM aldehyde was shown to be a plausible intermediate in the formation of acidic metabolites by experiments that indicated oxidation of this to TA was catalyzed by aldehyde oxidase derived from liver cytosolic fraction.
非甾体类抗雌激素他莫昔芬（TAM）在人和实验动物体内会发生广泛的生物转化。特别是，TAM的二甲氨基会发生N-去甲基化，并被羟基正式取代，分别生成主要代谢产物TAM胺和TAM醇。在本项针对去卵巢大鼠的研究中，TAM部分以其碱性侧链转化为氧乙酸部分所产生的代谢产物形式被消除。因此，经腹腔注射TAM后，从大鼠尿液中通过光谱鉴定出了TAM酸（TA）。在粪便提取物中未检测到TA。相比之下，仅从粪便提取物中检测并鉴定出了另一种代谢产物4-羟基TA（4HTA），这表明TA和4HTA的消除途径存在质的差异。对大鼠肝组分的研究表明，TAM醇是TAM转化为TA和4HTA过程中的中间代谢产物。在肝微粒体组分中，TAM醇转化为一种新的代谢产物TAM醛，该产物被分离出来并鉴定为其半卡巴腙衍生物。形成这种（衍生物）代谢产物以及将TA转化为4HTA所需的辅酶表明，这些转化是由细胞色素P450催化的。实验表明，这种醛氧化为TA是由源自肝细胞质组分的醛氧化酶催化的，这些实验表明TAM醛是形成酸性代谢产物的一种可能的中间体。
