TY - JOUR
T1 - Interactions of tamoxifen, N-desmethyltamoxifen and 4-hydroxytamoxifen with P-glycoprotein and CYP3A
AU - Bekaii-Saab, Tanios S.
AU - Perloff, Michael D.
AU - Weemhoff, James L.
AU - Greenblatt, David J.
AU - von Moltke, Lisa L.
PY - 2004/10
Y1 - 2004/10
N2 - 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 μM for tamoxifen; 26 μM for N-desmethyltamoxifen; and 7.4 μM 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 α -hydroxy-triazolam and 4-hydroxy-triazolam in human liver microsomes were, respectively: 23.5 (± 3.9) and 18.4 (± 5.3) μM for tamoxifen; 10.2 (± 1.7) and 9.2 (± 1.5) μM for N-desmethyltamoxifen; and 2.6 (± 0.5) and 2.7 (± 0.3) μ M 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.
AB - 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 μM for tamoxifen; 26 μM for N-desmethyltamoxifen; and 7.4 μM 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 α -hydroxy-triazolam and 4-hydroxy-triazolam in human liver microsomes were, respectively: 23.5 (± 3.9) and 18.4 (± 5.3) μM for tamoxifen; 10.2 (± 1.7) and 9.2 (± 1.5) μM for N-desmethyltamoxifen; and 2.6 (± 0.5) and 2.7 (± 0.3) μ M 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.
KW - CYP3A
KW - P-glycoprotein
KW - Tamoxifen
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U2 - 10.1002/bdd.411
DO - 10.1002/bdd.411
M3 - Article
C2 - 15386482
AN - SCOPUS:6444239304
SN - 0142-2782
VL - 25
SP - 283
EP - 289
JO - Biopharmaceutics and Drug Disposition
JF - Biopharmaceutics and Drug Disposition
IS - 7
ER -