Role and pharmacologic significance of cytochrome P-450 2D6 in oxidative metabolism of toremifene and tamoxifen

Juhyun Kim, Christopher C. Coss, Christina M. Barrett, Michael L. Mohler, Casey E. Bohl, Chien Ming Li, Yali He, Karen A. Veverka, James T. Dalton

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

We investigated the in vitro metabolism and estrogenic and antiestrogenic activity of toremifene (TOR), tamoxifen (TAM) and their metabolites to better understand the potential effects of cytochrome P-450 2D6 (CYP2D6) status on the activity of these drugs in women with breast cancer. The plasma concentrations of TOR and its N-desmethyl (NDM) and 4-hydroxy (4-OH) metabolites during steady-state dosing with TOR were also determined. Unlike TOR, TAM and its NDM metabolite were extensively oxidized to 4-OH TAM and 4-OH-NDM TAM by CYP2D6, and the rate of metabolism was affected by CYP2D6 status. 4-OH-NDM TOR concentrations were not measurable at steady state in plasma of subjects taking 80 mg of TOR. Molecular modeling provided insight into the lack of 4-hydroxylation of TOR by CYP2D6. The 4-OH and 4-OH-NDM metabolites of TOR and TAM bound to estrogen receptor (ER) subtypes with fourfold to 30-fold greater affinity were 35- to 187-fold more efficient at antagonizing ER transactivation and had antiestrogenic potency that was up to 360-fold greater than their parent drugs. Our findings suggest that variations in CYP2D6 metabolic capacity may cause significant differences in plasma concentrations of active TAM metabolites (i.e., 4-OH TAM and 4-OH-NDM TAM) and contribute to variable pharmacologic activity. Unlike TAM, the clinical benefits in subjects taking TOR to treat metastatic breast cancer would not likely be subject to allelic variation in CYP2D6 status or affected by coadministration of CYP2D6-inhibiting medications. What's new? Toremifene and tamoxifen are widely used in the treatment of metastatic breast cancer, but the potential effect on their pharmacologic activity of genetic variations in the enzymes responsible for their metabolism is not fully understood. In this study, variations in activity of the enzyme CYP2D6 were associated with significant differences in the metabolism of tamoxifen, but not toremifene. The variations may alter plasma concentrations of active tamoxifen metabolites, leading to unexpected toxicities and drug-drug interactions.

Original languageEnglish (US)
Pages (from-to)1475-1485
Number of pages11
JournalInternational Journal of Cancer
Volume132
Issue number6
DOIs
StatePublished - Mar 15 2013

Fingerprint

Toremifene
Tamoxifen
Cytochrome P-450 Enzyme System
Breast Neoplasms
Estrogen Receptors
Hydroxylation
Drug-Related Side Effects and Adverse Reactions
Drug Interactions
Pharmaceutical Preparations

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Kim, J., Coss, C. C., Barrett, C. M., Mohler, M. L., Bohl, C. E., Li, C. M., ... Dalton, J. T. (2013). Role and pharmacologic significance of cytochrome P-450 2D6 in oxidative metabolism of toremifene and tamoxifen. International Journal of Cancer, 132(6), 1475-1485. https://doi.org/10.1002/ijc.27794

Role and pharmacologic significance of cytochrome P-450 2D6 in oxidative metabolism of toremifene and tamoxifen. / Kim, Juhyun; Coss, Christopher C.; Barrett, Christina M.; Mohler, Michael L.; Bohl, Casey E.; Li, Chien Ming; He, Yali; Veverka, Karen A.; Dalton, James T.

In: International Journal of Cancer, Vol. 132, No. 6, 15.03.2013, p. 1475-1485.

Research output: Contribution to journalArticle

Kim, J, Coss, CC, Barrett, CM, Mohler, ML, Bohl, CE, Li, CM, He, Y, Veverka, KA & Dalton, JT 2013, 'Role and pharmacologic significance of cytochrome P-450 2D6 in oxidative metabolism of toremifene and tamoxifen', International Journal of Cancer, vol. 132, no. 6, pp. 1475-1485. https://doi.org/10.1002/ijc.27794
Kim, Juhyun ; Coss, Christopher C. ; Barrett, Christina M. ; Mohler, Michael L. ; Bohl, Casey E. ; Li, Chien Ming ; He, Yali ; Veverka, Karen A. ; Dalton, James T. / Role and pharmacologic significance of cytochrome P-450 2D6 in oxidative metabolism of toremifene and tamoxifen. In: International Journal of Cancer. 2013 ; Vol. 132, No. 6. pp. 1475-1485.
@article{090f13c9c69647bf9beafb2e6491942d,
title = "Role and pharmacologic significance of cytochrome P-450 2D6 in oxidative metabolism of toremifene and tamoxifen",
abstract = "We investigated the in vitro metabolism and estrogenic and antiestrogenic activity of toremifene (TOR), tamoxifen (TAM) and their metabolites to better understand the potential effects of cytochrome P-450 2D6 (CYP2D6) status on the activity of these drugs in women with breast cancer. The plasma concentrations of TOR and its N-desmethyl (NDM) and 4-hydroxy (4-OH) metabolites during steady-state dosing with TOR were also determined. Unlike TOR, TAM and its NDM metabolite were extensively oxidized to 4-OH TAM and 4-OH-NDM TAM by CYP2D6, and the rate of metabolism was affected by CYP2D6 status. 4-OH-NDM TOR concentrations were not measurable at steady state in plasma of subjects taking 80 mg of TOR. Molecular modeling provided insight into the lack of 4-hydroxylation of TOR by CYP2D6. The 4-OH and 4-OH-NDM metabolites of TOR and TAM bound to estrogen receptor (ER) subtypes with fourfold to 30-fold greater affinity were 35- to 187-fold more efficient at antagonizing ER transactivation and had antiestrogenic potency that was up to 360-fold greater than their parent drugs. Our findings suggest that variations in CYP2D6 metabolic capacity may cause significant differences in plasma concentrations of active TAM metabolites (i.e., 4-OH TAM and 4-OH-NDM TAM) and contribute to variable pharmacologic activity. Unlike TAM, the clinical benefits in subjects taking TOR to treat metastatic breast cancer would not likely be subject to allelic variation in CYP2D6 status or affected by coadministration of CYP2D6-inhibiting medications. What's new? Toremifene and tamoxifen are widely used in the treatment of metastatic breast cancer, but the potential effect on their pharmacologic activity of genetic variations in the enzymes responsible for their metabolism is not fully understood. In this study, variations in activity of the enzyme CYP2D6 were associated with significant differences in the metabolism of tamoxifen, but not toremifene. The variations may alter plasma concentrations of active tamoxifen metabolites, leading to unexpected toxicities and drug-drug interactions.",
author = "Juhyun Kim and Coss, {Christopher C.} and Barrett, {Christina M.} and Mohler, {Michael L.} and Bohl, {Casey E.} and Li, {Chien Ming} and Yali He and Veverka, {Karen A.} and Dalton, {James T.}",
year = "2013",
month = "3",
day = "15",
doi = "10.1002/ijc.27794",
language = "English (US)",
volume = "132",
pages = "1475--1485",
journal = "International Journal of Cancer",
issn = "0020-7136",
publisher = "Wiley-Liss Inc.",
number = "6",

}

TY - JOUR

T1 - Role and pharmacologic significance of cytochrome P-450 2D6 in oxidative metabolism of toremifene and tamoxifen

AU - Kim, Juhyun

AU - Coss, Christopher C.

AU - Barrett, Christina M.

AU - Mohler, Michael L.

AU - Bohl, Casey E.

AU - Li, Chien Ming

AU - He, Yali

AU - Veverka, Karen A.

AU - Dalton, James T.

PY - 2013/3/15

Y1 - 2013/3/15

N2 - We investigated the in vitro metabolism and estrogenic and antiestrogenic activity of toremifene (TOR), tamoxifen (TAM) and their metabolites to better understand the potential effects of cytochrome P-450 2D6 (CYP2D6) status on the activity of these drugs in women with breast cancer. The plasma concentrations of TOR and its N-desmethyl (NDM) and 4-hydroxy (4-OH) metabolites during steady-state dosing with TOR were also determined. Unlike TOR, TAM and its NDM metabolite were extensively oxidized to 4-OH TAM and 4-OH-NDM TAM by CYP2D6, and the rate of metabolism was affected by CYP2D6 status. 4-OH-NDM TOR concentrations were not measurable at steady state in plasma of subjects taking 80 mg of TOR. Molecular modeling provided insight into the lack of 4-hydroxylation of TOR by CYP2D6. The 4-OH and 4-OH-NDM metabolites of TOR and TAM bound to estrogen receptor (ER) subtypes with fourfold to 30-fold greater affinity were 35- to 187-fold more efficient at antagonizing ER transactivation and had antiestrogenic potency that was up to 360-fold greater than their parent drugs. Our findings suggest that variations in CYP2D6 metabolic capacity may cause significant differences in plasma concentrations of active TAM metabolites (i.e., 4-OH TAM and 4-OH-NDM TAM) and contribute to variable pharmacologic activity. Unlike TAM, the clinical benefits in subjects taking TOR to treat metastatic breast cancer would not likely be subject to allelic variation in CYP2D6 status or affected by coadministration of CYP2D6-inhibiting medications. What's new? Toremifene and tamoxifen are widely used in the treatment of metastatic breast cancer, but the potential effect on their pharmacologic activity of genetic variations in the enzymes responsible for their metabolism is not fully understood. In this study, variations in activity of the enzyme CYP2D6 were associated with significant differences in the metabolism of tamoxifen, but not toremifene. The variations may alter plasma concentrations of active tamoxifen metabolites, leading to unexpected toxicities and drug-drug interactions.

AB - We investigated the in vitro metabolism and estrogenic and antiestrogenic activity of toremifene (TOR), tamoxifen (TAM) and their metabolites to better understand the potential effects of cytochrome P-450 2D6 (CYP2D6) status on the activity of these drugs in women with breast cancer. The plasma concentrations of TOR and its N-desmethyl (NDM) and 4-hydroxy (4-OH) metabolites during steady-state dosing with TOR were also determined. Unlike TOR, TAM and its NDM metabolite were extensively oxidized to 4-OH TAM and 4-OH-NDM TAM by CYP2D6, and the rate of metabolism was affected by CYP2D6 status. 4-OH-NDM TOR concentrations were not measurable at steady state in plasma of subjects taking 80 mg of TOR. Molecular modeling provided insight into the lack of 4-hydroxylation of TOR by CYP2D6. The 4-OH and 4-OH-NDM metabolites of TOR and TAM bound to estrogen receptor (ER) subtypes with fourfold to 30-fold greater affinity were 35- to 187-fold more efficient at antagonizing ER transactivation and had antiestrogenic potency that was up to 360-fold greater than their parent drugs. Our findings suggest that variations in CYP2D6 metabolic capacity may cause significant differences in plasma concentrations of active TAM metabolites (i.e., 4-OH TAM and 4-OH-NDM TAM) and contribute to variable pharmacologic activity. Unlike TAM, the clinical benefits in subjects taking TOR to treat metastatic breast cancer would not likely be subject to allelic variation in CYP2D6 status or affected by coadministration of CYP2D6-inhibiting medications. What's new? Toremifene and tamoxifen are widely used in the treatment of metastatic breast cancer, but the potential effect on their pharmacologic activity of genetic variations in the enzymes responsible for their metabolism is not fully understood. In this study, variations in activity of the enzyme CYP2D6 were associated with significant differences in the metabolism of tamoxifen, but not toremifene. The variations may alter plasma concentrations of active tamoxifen metabolites, leading to unexpected toxicities and drug-drug interactions.

UR - http://www.scopus.com/inward/record.url?scp=84872927511&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84872927511&partnerID=8YFLogxK

U2 - 10.1002/ijc.27794

DO - 10.1002/ijc.27794

M3 - Article

VL - 132

SP - 1475

EP - 1485

JO - International Journal of Cancer

JF - International Journal of Cancer

SN - 0020-7136

IS - 6

ER -