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Comprehensive evaluation of tamoxifen sequential biotransformation by the human cytochrome P450 system in vitro: prominent roles for CYP3A and CYP2D6.
J Pharmacol Exp Ther. 2004 Sep; 310(3):1062-75.JP

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 alpha -, 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 alpha-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.

Authors+Show Affiliations

Indiana University School of Medicine, Department of Medicine/Division of Clinical Pharmacology, 1001 West 10th street, WD Myers Bldg., W7123, Indianapolis, IN 46202, USA. zdesta@iupui.eduNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

15159443

Citation

Desta, Zeruesenay, et al. "Comprehensive Evaluation of Tamoxifen Sequential Biotransformation By the Human Cytochrome P450 System in Vitro: Prominent Roles for CYP3A and CYP2D6." The Journal of Pharmacology and Experimental Therapeutics, vol. 310, no. 3, 2004, pp. 1062-75.
Desta Z, Ward BA, Soukhova NV, et al. Comprehensive evaluation of tamoxifen sequential biotransformation by the human cytochrome P450 system in vitro: prominent roles for CYP3A and CYP2D6. J Pharmacol Exp Ther. 2004;310(3):1062-75.
Desta, Z., Ward, B. A., Soukhova, N. V., & Flockhart, D. A. (2004). Comprehensive evaluation of tamoxifen sequential biotransformation by the human cytochrome P450 system in vitro: prominent roles for CYP3A and CYP2D6. The Journal of Pharmacology and Experimental Therapeutics, 310(3), 1062-75.
Desta Z, et al. Comprehensive Evaluation of Tamoxifen Sequential Biotransformation By the Human Cytochrome P450 System in Vitro: Prominent Roles for CYP3A and CYP2D6. J Pharmacol Exp Ther. 2004;310(3):1062-75. PubMed PMID: 15159443.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Comprehensive evaluation of tamoxifen sequential biotransformation by the human cytochrome P450 system in vitro: prominent roles for CYP3A and CYP2D6. AU - Desta,Zeruesenay, AU - Ward,Bryan A, AU - Soukhova,Nadia V, AU - Flockhart,David A, Y1 - 2004/05/24/ PY - 2004/5/26/pubmed PY - 2004/11/2/medline PY - 2004/5/26/entrez SP - 1062 EP - 75 JF - The Journal of pharmacology and experimental therapeutics JO - J Pharmacol Exp Ther VL - 310 IS - 3 N2 - 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 alpha -, 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 alpha-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. SN - 0022-3565 UR - https://www.unboundmedicine.com/medline/citation/15159443/Comprehensive_evaluation_of_tamoxifen_sequential_biotransformation_by_the_human_cytochrome_P450_system_in_vitro:_prominent_roles_for_CYP3A_and_CYP2D6_ L2 - https://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=15159443 DB - PRIME DP - Unbound Medicine ER -