title: Interactions of tamoxifen, N-desmethyltamoxifen and 4-hydroxytamoxifen with P-glycoprotein and CYP3A.
abstract: The effects of tamoxifen, N-desmethyltamoxifen and 4-hydroxytamoxifen on transport attributable to P-glycoprotein were studied using Caco-2 cell monolayers in a transwell system, with rhodamine-123 as an index substrate for inhibition studies. The three compounds did not demonstrate differential flux between basal-apical and apical-basal directions in Caco-2 monolayers. The mean IC50 values for inhibition of rhodamine-123 transport were: 29 microM for tamoxifen; 26 microM for N-desmethyltamoxifen; and 7.4 microM for 4-hydroxytamoxifen. The three compounds were also evaluated as potential inhibitors of human CYP3A based on an in vitro model using triazolam hydroxylation by human liver microsomes as an index reaction. Mean (+/-SE) IC50 values versus formation of alpha-hydroxy-triazolam and 4-hydroxy-triazolam in human liver microsomes were, respectively: 23.5 (+/-3.9) and 18.4 (+/-5.3) microM for tamoxifen; 10.2 (+/-1.7) and 9.2 (+/-1.5) microM for N-desmethyltamoxifen; and 2.6 (+/-0.5) and 2.7 (+/-0.3) microM for 4-hydroxytamoxifen. Thus, tamoxifen, N-desmethyltamoxifen and 4-hydroxytamoxifen, do not appear to be substrates for transport by P-glycoprotein. However, tamoxifen has the potential to inhibit transport mediated by P-glycoprotein as well as CYP3A-mediated metabolism. Inhibitory effects of the principal metabolites, N-desmethyltamoxifen and 4-hydroxytamoxifen, may exceed those of the parent drug. Tamoxifen, and possibly its metabolites, may have the potential to cause drug interactions by inhibiting both drug transport and metabolism. This possibility requires further evaluation in clinical studies.
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston, MA 02111, USA.
authors.forename: Tanios S
authors.initials: TS
authors.lastname: Bekaii-Saab
authors.forename: Michael D
authors.initials: MD
authors.lastname: Perloff
authors.forename: James L
authors.initials: JL
authors.lastname: Weemhoff
authors.forename: David J
authors.initials: DJ
authors.lastname: Greenblatt
authors.forename: Lisa L
authors.initials: LL
authors.lastname: von Moltke
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000502:physiology; D001692:Biological Transport; D018938:Caco-2 Cells; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology; D004347:Drug Interactions; D006801:Humans; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D065607:Cytochrome P-450 Enzyme Inhibitors; D013629:Tamoxifen; C016601:afimoxifene; D003577:Cytochrome P-450 Enzyme System; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C028787:N-desmethyltamoxifen