Metabolism of the 4-iodo derivative of tamoxifen by isolated rat hepatocytes: Demonstration that the iodine atom reduces metabolic conversion and identification of four metabolites

doi:10.1016/0006-2952(90)90723-X

Biochemical Pharmacology

Volume 40, Issue 10, 15 November 1990, Pages 2277-2283

https://doi.org/10.1016/0006-2952(90)90723-X Get rights and content

Abstract

The 4-iodo derivative of tamoxifen, which has been reported to possess improved oestrogen receptor affinity and effectiveness as an inhibitor of breast tumour cell growth in vitro, was metabolized by hepatocytes isolated from rats pretreated with phenobarbital four times more slowly than tamoxifen and there was very little formation of glucuronide conjugates. Four principal metabolites were isolated. Examination of mass spectra revealed desmethyl-4-iodotamoxiffen, N-oxide, and α-hydroxydesmethyl-4-iodotamoxifen {4-[4-[2-(methylamino)ethoxy]phenyl]-4-(4-iodophenyl)-3-phenyl)-3-(Z)-en-2-ol}. Their identification was confirmed by comparison with synthesized samples. The structure of the fourth metabolite, 4′-hydroxy-4-iodotamoxifen was revealed by ¹H NMR spectroscopy. The iodophenyl moiety is thus retained in all the metabolites. The iodine atom not only blocks metabolism in its vicinity but also reduced the rate of side-chain demethylation and N-oxidation by three-fold. It can be predicted from this study that the presence of the iodine atom should give the compound a greater duration of action in vivo.

References (20)

N. Binart et al.
Monohydroxytamoxifen: An antioestrogen with a high affinity for the chick oviduct oestrogen receptor
Biophys Res Commun
(1979)
R. McCague et al.
Metabolism of tamoxifen by isolated rat hepatocytes. Identification of the glucuronide of 4-hydroxytamoxifen
Biochem Pharmacol
(1990)
I.B. Parr et al.
Metabolism of tamoxifen by isolated rat hepatocytes. Identification of 1-[4-(2-hydroxyethoxy)phenyl]-1-(4-hydroxyphenyl)-2-phenyl-1-butene and the dependence of N-oxidation on oxygen availability
Biochem Pharmacol
(1987)
A.B. Foster et al.
Metabolism of 4-hydroxyandrost-4-ene-3,17-dione by rat hepatocytes
J Steroid Biochem
(1986)
A.B. Foster et al.
Metabolism of tamoxifen by rat liver microsomes, formation of the N-oxide, a new metabolite
Biochem Pharmacol
(1980)
R. McCague et al.
Aspects of metabolism of tamoxifen by rat liver microsomes: identification of a new metabolite: E-1-[4-(2-dimethylaminoethoxy)-phenyl-1,2-diphenyl-1-buten-3-ol N-oxide
Biochem Pharmacol
(1986)
D.J. Bates et al.
Metabolism of tamoxifen by isolated rat hepatocytes: antioestrogenic activity of tamoxifen N-oxide
Biochem Pharmacol
(1982)
V.C. Jordan et al.
Evaluation of the antitumour activity of the non-steroidal antioestrogen monohydroxytamoxifen in the DMBA-induced rat mammary carcinoma model
Eur J Cancer
(1980)
S.J. Brandes et al.
Fundamental considerations in the design of fluorine-18 labelled progestins and androgens as imaging agents for receptor-positive tumors of the breast and prostate
Nucl Med Biol
(1988)
R. McCague et al.
4-Substituted derivatives of tamoxifen: dependence of antiestrogenicity on the 4-substituent
J Med Chem
(1989)

There are more references available in the full text version of this article.

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Idoxifene was also developed to improve potency and reduce side effects that were common to tamoxifen. The addition of an iodine group to the 4 position was expected to reduce clearance, allowing for a longer half-life and a longer duration of action and as expected, idoxifene displayed a 2.5 times slower rate of metabolism (McCague, Parr, & Haynes, 1990; Osborne, Wiebe, McGuire, Ciocca, & DeGregorio, 1992). Idoxifene showed some agonist activity in the uterus in preclinical models (Nuttall et al., 1998), although, in a phase II study, the endometrial profile of tamoxifen and idoxifene was similar (Johnston et al., 2004).
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Idoxifene (pyrrolidino-4-iodofamaxifene), a 4-iodinated analog of tamoxifen, is a novel selective estrogen receptor modulator (SERM) that was created in an effort to produce an antiestrogen with greater antiestrogenic but lower estrogenic activity than tamoxifen [6, 7]. Compared with tamoxifen, idoxifene has been found to be metabolically more stable [6, 8] and to have a higher relative binding affinity for the estrogen receptor (ER) [7, 9]. Idoxifene has greater in vitro antitumor activity than tamoxifen [7, 10].
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Idoxifene was both active and well tolerated in postmenopausal women with metastatic breast cancer. Idoxifene had similar efficacy and toxicity to tamoxifen in this randomized comparison.
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Research paperMetabolism of the 4-iodo derivative of tamoxifen by isolated rat hepatocytes: Demonstration that the iodine atom reduces metabolic conversion and identification of four metabolites

Abstract

Biophys Res Commun

Biochem Pharmacol

Biochem Pharmacol

J Steroid Biochem

Biochem Pharmacol

Biochem Pharmacol

Biochem Pharmacol

Eur J Cancer

Nucl Med Biol

4-Substituted derivatives of tamoxifen: dependence of antiestrogenicity on the 4-substituent

J Med Chem

Research paper
Metabolism of the 4-iodo derivative of tamoxifen by isolated rat hepatocytes: Demonstration that the iodine atom reduces metabolic conversion and identification of four metabolites