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 language||English (US)|
|Journal||Clinical Pharmacology and Therapeutics|
|State||Published - Dec 1 2001|
ASJC Scopus subject areas
- Pharmacology (medical)