Abstract
We performed comprehensive kinetic, inhibition, and correlation analyses in human liver microsomes and experiments in expressed human cytochromes P450 (P450s) to identify primary and secondary metabolic routes of tamoxifen (TAM) and the P450s catalyzing these reactions at therapeutically relevant concentrations. N-Desmethyl-TAM formation catalyzed by CYP3A4/5 was quantitatively the major primary metabolite of TAM; 4-hydroxy-TAM formation catalyzed by CYP2D6 (and other P450s) represents a minor route. Other minor primary metabolites include α -, 3-, and 4′-hydroxyTAM and one unidentified metabolite (M-I) and were primarily catalyzed by CYP3A4, CYP3A5, CYP2B6/2C19, and CYP3A4, respectively. TAM secondary metabolism was examined using N-desmethyl- and 4-hydroxy-TAM as intermediate substrates. N-Desmethyl-TAM was predominantly biotransformed to α-hydroxy N-desmethyl-, N-didesmethyl-, and 4-hydroxy N-desmethyl-TAM (endoxifen), whereas 4-hydroxy-TAM was converted to 3,4-dihydroxyTAM and endoxifen. Except for the biotransformation of N-desmethyl-TAM to endoxifen, which was exclusively catalyzed by CYP2D6, all other routes of N-desmethyl- and 4-hydroxy-TAM biotransformation were catalyzed predominantly by the CYP3A subfamily. TAM and its primary metabolites undergo extensive oxidation, principally by CYP3A and CYP2D6 to metabolites that exhibit a range of pharmacological effects. Variable activity of these P450s, brought about by genetic polymorphisms and drug interactions, may alter the balance of TAM effects in vivo.
Footnotes
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The research was supported by Pharmacogenetics Network Grant U-01 GM61373 and by Clinical Pharmacology Training Grant T32 GM 56898 from the National Institute of General Medical Sciences (Bethesda, MD).
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.104.065607.
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ABBREVIATIONS: TAM, tamoxifen; ER, estrogen receptor; endoxifen, 4-hydroxy-N-desmethyl-tamoxifen; P450, cytochrome P450; HPLC, high-performance liquid chromatography; HLM, human liver microsome; CLint, intrinsic clearances; TEPA, N,N′,N′′-triethylene phosphoramide.
- Received January 16, 2004.
- Accepted May 24, 2004.
- The American Society for Pharmacology and Experimental Therapeutics
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