title: Multigene and Drug Interaction Approach for Tamoxifen Metabolite Patterns Reveals Possible Involvement of CYP2C9, CYP2C19, and ABCB1.
abstract: Tamoxifen is metabolically activated to 4-hydroxytamoxifen and endoxifen by cytochrome P450 (CYP). CYP phenotypes have been correlated to tamoxifen outcomes, but few have considered drug interactions or combinations of genes. Fewer still have considered ABCB1, which encodes P-glycoprotein and transports active tamoxifen metabolites. We compared the concentrations of tamoxifen and metabolites in 116 breast cancer patients with predicted phenotypes for CYP2D6, CYP3A4, CYP3A5, CYP2C9, CYP2C19, and ABCB1 genotypes. A significant correlation between CYP2D6 phenotypes and tamoxifen metabolites was seen, strongest for endoxifen (P < .0001). Statistical fit of the data improved when using gene activity scores adjusted for known drug interactions. Concentration of tamoxifen was significantly higher (P = .02) for patients taking a CYP2C19 inhibitor. No significant relationships were found for other genes unless patients were subgrouped according to CYP2D6 phenotypes or ABCB1 genotypes. Lower concentrations of endoxifen and endoxifen/4-hydroxytamoxifen ratios were seen with impaired CYP2C9 (P = .05 and P = .03, respectively) if patients had the same CYP2D6 phenotype and were not taking a CYP2D6 or CYP2C19 inhibitor. Lower concentrations of 4-hydroxytamoxifen were seen for impaired CYP2C19 when ABCB1 SNP3435 was nonvariant (P = .04). With 3 impaired CYP phenotypes, endoxifen concentrations were lower than if only CYP2D6 was impaired (P = .05). When CYP2D6 was impaired, ABCB1 3435 CC (rs1045642) was associated with significantly higher endoxifen (P = .03). Thus, impairment in CYP2C9, CYP2C19, or ABCB1 contributes to a lower steady-state endoxifen concentration at the dose studied. These studies represent an improved way of examining relationships between pharmacogenetics, drug concentrations, and clinical outcomes and warrants study in larger populations.
authors.affiliation: Department of Pathology, University of Utah, Salt Lake City, UT, USA.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Powers
authors.affiliation: Department of Medicine, Huntsman Cancer Institute, University of Utah Health Sciences Center, Salt Lake City, UT, USA.
authors.forename: Saundra S
authors.initials: SS
authors.lastname: Buys
authors.affiliation: Department of Pharmacy, Huntsman Cancer Institute, University of Utah Health Sciences Center, Salt Lake City, UT, USA.
authors.forename: Deborah
authors.initials: D
authors.lastname: Fletcher
authors.affiliation: ARUP Institute for Clinical and Experimental Pathology, Salt Lake City, UT, USA.
authors.forename: Roberta
authors.initials: R
authors.lastname: Melis
authors.affiliation: Department of Pathology, University of Utah, Salt Lake City, UT, USA.|ARUP Institute for Clinical and Experimental Pathology, Salt Lake City, UT, USA.
authors.forename: Kamisha L
authors.initials: KL
authors.lastname: Johnson-Davis
authors.affiliation: Department of Pathology, University of Utah, Salt Lake City, UT, USA.|ARUP Institute for Clinical and Experimental Pathology, Salt Lake City, UT, USA.
authors.forename: Elaine
authors.initials: E
authors.lastname: Lyon
authors.affiliation: ARUP Institute for Clinical and Experimental Pathology, Salt Lake City, UT, USA.
authors.forename: Elisabeth M
authors.initials: EM
authors.lastname: Malmberg
authors.affiliation: Department of Pathology, University of Utah, Salt Lake City, UT, USA.|ARUP Institute for Clinical and Experimental Pathology, Salt Lake City, UT, USA.
authors.forename: Gwendolyn A
authors.initials: GA
authors.lastname: McMillin
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018931:Antineoplastic Agents, Hormonal / Q000378:metabolism* / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D065731:Cytochrome P-450 CYP2C19 / Q000235:genetics / Q000378:metabolism*; D065729:Cytochrome P-450 CYP2C9 / Q000235:genetics / Q000378:metabolism*; D004347:Drug Interactions / Q000502:physiology; D005260:Female; D006801:Humans; D008875:Middle Aged; D013629:Tamoxifen / Q000378:metabolism* / Q000627:therapeutic use
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D018931:Antineoplastic Agents, Hormonal; D013629:Tamoxifen; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19
keywords: ABCB1; CYP; drug interactions; gene activity scoring; metabolites; tamoxifen