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Interactions of tamoxifen, N‐desmethyltamoxifen and 4‐hydroxytamoxifen with P‐glycoprotein and CYP3A
Author(s) -
BekaiiSaab Tanios S.,
Perloff Michael D.,
Weemhoff James L.,
Greenblatt David J.,
von Moltke Lisa L.
Publication year - 2004
Publication title -
biopharmaceutics and drug disposition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.419
H-Index - 58
eISSN - 1099-081X
pISSN - 0142-2782
DOI - 10.1002/bdd.411
Subject(s) - chemistry , rhodamine 123 , pharmacology , tamoxifen , biochemistry , microsome , p glycoprotein , in vitro , biology , multiple drug resistance , genetics , cancer , breast cancer , antibiotics
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 IC 50 values for inhibition of rhodamine‐123 transport were: 29 µ M for tamoxifen; 26 µ M for N‐desmethyltamoxifen; and 7.4 µ M 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) IC 50 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) µ M for tamoxifen; 10.2 (±1.7) and 9.2 (±1.5) µ M 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. Copyright © 2004 John Wiley & Sons, Ltd.