Characterization of tamoxifen metabolism to a novel, putative active metabolite

A. M. Morocho, Zeruesenay Desta, G. M. Wu, N. V. Soukova, J. M. Rae, D. A. Flockhart

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

We studied the formation of a putative active metabolite, 4-hydroxy-N-desmethyltamoxifen (4-OH-NDM), using human liver microsomes (HLMs) and recombinant human CYP450. We separated 4-OH-NDM by HPLC with fluorescence detection after in-line UV-derivatization. The molecular mass was determined by LC-MS and is consistent with that of 4-OH-NDM. Finally, we chemically synthesized 4-OH-NDM to confirm its identity. In microsomes 4-OH-NDM was markedly formed when NDM and 4-OHT were used as substrates, however, it was undetectable when TAM was used. This suggests that 4-OH-NDM is a secondary rather than a primary metabolite. The formation of 4-OH-NDM from NDM and 4-OHT was catalyzed primarily by polymorphic CYP2D6 and CYP3A (Kms 3.8 μM and 5.8 μM, respectively). These data are consistent with our clinical results indicating that CYP2D6 phenotype and paroxetine co-administration decrease the plasma concentrations of 4-OH-NDM.

Original languageEnglish (US)
JournalClinical Pharmacology and Therapeutics
Volume69
Issue number2
StatePublished - 2001
Externally publishedYes

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Tamoxifen
Cytochrome P-450 CYP2D6
Cytochrome P-450 CYP3A
Paroxetine
hydroxide ion
Liver Microsomes
Microsomes
Fluorescence
High Pressure Liquid Chromatography
Phenotype

ASJC Scopus subject areas

  • Pharmacology

Cite this

Morocho, A. M., Desta, Z., Wu, G. M., Soukova, N. V., Rae, J. M., & Flockhart, D. A. (2001). Characterization of tamoxifen metabolism to a novel, putative active metabolite. Clinical Pharmacology and Therapeutics, 69(2).

Characterization of tamoxifen metabolism to a novel, putative active metabolite. / Morocho, A. M.; Desta, Zeruesenay; Wu, G. M.; Soukova, N. V.; Rae, J. M.; Flockhart, D. A.

In: Clinical Pharmacology and Therapeutics, Vol. 69, No. 2, 2001.

Research output: Contribution to journalArticle

Morocho, AM, Desta, Z, Wu, GM, Soukova, NV, Rae, JM & Flockhart, DA 2001, 'Characterization of tamoxifen metabolism to a novel, putative active metabolite', Clinical Pharmacology and Therapeutics, vol. 69, no. 2.
Morocho, A. M. ; Desta, Zeruesenay ; Wu, G. M. ; Soukova, N. V. ; Rae, J. M. ; Flockhart, D. A. / Characterization of tamoxifen metabolism to a novel, putative active metabolite. In: Clinical Pharmacology and Therapeutics. 2001 ; Vol. 69, No. 2.
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AU - Desta, Zeruesenay

AU - Wu, G. M.

AU - Soukova, N. V.

AU - Rae, J. M.

AU - Flockhart, D. A.

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N2 - We studied the formation of a putative active metabolite, 4-hydroxy-N-desmethyltamoxifen (4-OH-NDM), using human liver microsomes (HLMs) and recombinant human CYP450. We separated 4-OH-NDM by HPLC with fluorescence detection after in-line UV-derivatization. The molecular mass was determined by LC-MS and is consistent with that of 4-OH-NDM. Finally, we chemically synthesized 4-OH-NDM to confirm its identity. In microsomes 4-OH-NDM was markedly formed when NDM and 4-OHT were used as substrates, however, it was undetectable when TAM was used. This suggests that 4-OH-NDM is a secondary rather than a primary metabolite. The formation of 4-OH-NDM from NDM and 4-OHT was catalyzed primarily by polymorphic CYP2D6 and CYP3A (Kms 3.8 μM and 5.8 μM, respectively). These data are consistent with our clinical results indicating that CYP2D6 phenotype and paroxetine co-administration decrease the plasma concentrations of 4-OH-NDM.

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