Tamoxifen and toremifene concentrations in plasma are greatly decreased by rifampin*

Kivistö, Kari T.; Villikka, Kirsti; Nyman, Leena; Anttila, Markku; Neuvonen, Pertti J.

doi:10.1016/s0009-9236(98)90055-8

Cited by 43 publications

(30 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…BFC is a fluorescent probe for CYP3A activity for use in high-throughput screens for CYP3A inhibitors (Stresser et al, 2000). Finally, the antiestrogen TAM is a CYP3A substrate (Kivisto et al, 1998) widely used in the adjuvant therapy of breast cancer in women.…”

Section: Discussionmentioning

confidence: 99%

Comparative Metabolic Capabilities of CYP3A4, CYP3A5, and CYP3A7

et al. 2002

View full text Add to dashboard Cite

ABSTRACT:The human cytochromes P450 (P450) CYP3A contribute to the biotransformation of 50% of oxidatively metabolized drugs. The predominant hepatic form is CYP3A4, but recent evidence indicates that CYP3A5 contributes more significantly to the total liver CYP3A than was originally thought. CYP3A7 is the major fetal form and is rarely expressed in adults. To compare the metabolic capabilities of CYP3A forms for 10 substrates, incubations were performed using a consistent molar ratio (1:7:9) of recombinant CYP3A, P450 reductase, and cytochrome b5. A wide range of substrate concentrations was examined to determine the best fit to kinetic models for metabolite formation. In general, K m or S 50 values for the substrates were 3 to 4 times lower for CYP3A4 than for CYP3A5 or CYP3A7. For a more direct comparison of these P450 forms, clearance to the metabolites was determined as a linear relationship of rate of metabolite formation for the lowest substrate concentrations examined. The clearance for 1-hydroxy midazolam formation at low substrate concentrations was similar for CYP3A4 and CYP3A5. For CYP3A5 versus CYP3A4, clearance values at low substrate concentrations were 2 to 20 times lower for the other biotransformations. The clearance values for CYP3A7-catalyzed metabolite formation at low substrate concentrations were substantially lower than for CYP3A4 or CYP3A5, except for clarithromycin, 4-OH triazolam, and N-desmethyl diltiazem (CYP3A5 Ϸ CYP3A7). The CYP3A forms demonstrated regioselective differences in some of the biotransformations. These results demonstrate an equal or reduced metabolic capability for CYP3A5 compared with CYP3A4 and a significantly lower capability for CYP3A7.

show abstract

Section: Discussionmentioning

confidence: 99%

Comparative Metabolic Capabilities of CYP3A4, CYP3A5, and CYP3A7

et al. 2002

View full text Add to dashboard Cite

show abstract

“…Of note, a marked increase of TAM N-demethylation has been reported when healthy volunteers were pretreated with rifampin (Kivisto et al, 1998), a drug known to induce CYP3A and other P450s (but not CYP2D6). In systems that consist of multiple P450s (e.g., HLMs and in vivo in humans), the contribution of CYP2D6 in TAM N-demethylation appears to be minimal.…”

Section: Hg112mentioning

confidence: 96%

Comprehensive Evaluation of Tamoxifen Sequential Biotransformation by the Human Cytochrome P450 System in Vitro: Prominent Roles for CYP3A and CYP2D6

Desta

Ward

Soukhova

et al. 2004

J Pharmacol Exp Ther

584

484

View full text Add to dashboard Cite

We performed comprehensive kinetic, inhibition, and correlation analyses in human liver microsomes and experiments in expressed human cytochromes P450 (P450s) to identify primary and secondary metabolic routes of tamoxifen (TAM) and the P450s catalyzing these reactions at therapeutically relevant concentrations. N-Desmethyl-TAM formation catalyzed by CYP3A4/5 was quantitatively the major primary metabolite of TAM; 4-hydroxy-TAM formation catalyzed by CYP2D6 (and other P450s) represents a minor route. Other minor primary metabolites include ␣ -, 3-, and 4Ј-hydroxyTAM and one unidentified metabolite (M-I) and were primarily catalyzed by CYP3A4, CYP3A5, CYP2B6/2C19, and CYP3A4, respectively. TAM secondary metabolism was examined using N-desmethyland 4-hydroxy-TAM as intermediate substrates. N-Desmethyl-TAM was predominantly biotransformed to ␣-hydroxy N-desmethyl-, N-didesmethyl-, and 4-hydroxy N-desmethyl-TAM (endoxifen), whereas 4-hydroxy-TAM was converted to 3,4-dihydroxyTAM and endoxifen. Except for the biotransformation of N-desmethyl-TAM to endoxifen, which was exclusively catalyzed by CYP2D6, all other routes of N-desmethyl-and 4-hydroxy-TAM biotransformation were catalyzed predominantly by the CYP3A subfamily. TAM and its primary metabolites undergo extensive oxidation, principally by CYP3A and CYP2D6 to metabolites that exhibit a range of pharmacological effects. Variable activity of these P450s, brought about by genetic polymorphisms and drug interactions, may alter the balance of TAM effects in vivo.

show abstract

“…The amount of tamoxifen metabolites formed is highly variable between individual patients. This can be attributed on the one hand to the relatively large number of inducible and polymorphic CYPs involved in tamoxifen metabolism and on the other hand to modulating effects of co-medication [9][10][11].…”

Section: Introductionmentioning

confidence: 99%

TGFβ2 and TβRII are valid molecular biomarkers for the antiproliferative effects of tamoxifen and tamoxifen metabolites in breast cancer cells

Buck

Coller

Mürdter

et al. 2007

Breast Cancer Res Treat

View full text Add to dashboard Cite

Response to treatment with the antiestrogen tamoxifen is variable and at least partially due to its highly complex metabolism. Tamoxifen is transformed by polymorphic and inducible cytochrome P450 enzymes to a large number of metabolites with varying biological activities. The estrogen receptor dependent growth inhibitory effect of antiestrogens is mediated by activation of antiproliferative Transforming Growth Factor beta (TGFbeta) signal transduction pathways. The aim of the present study was to establish if TGFbeta2 or TGFbeta receptor II (TbetaRII), could be used as markers to assess the pharmacological potency of tamoxifen and its metabolites. Consequently, we analyzed the growth inhibitory effect of tamoxifen and its major metabolites and explored whether it correlated with their capacity to induce TGFbeta2 and TbetaRII expression. Human breast cancer cells (MCF-7 and T47D) were treated with tamoxifen and tamoxifen metabolites and mRNA expression of TGFbeta2 and TbetaRII was analyzed by quantitative RT-PCR. Only two metabolites 4-hydroxytamoxifen and N-desmethyl-4-hydroxytamoxifen had significant antiproliferative activity and were able to induce TGFbeta2 and TbetaRII. Plasma concentrations of these metabolites are usually very low in patients. However, even minor growth inhibitory effects at concentrations which are below the limit of quantification in plasma samples resulted in clearly discernible effects on expression of TGFbeta2 and TbetaRII. Taken together, our data demonstrate that TGFbeta2 and TbetaRII are very specific and sensitive biomarkers for the antiestrogenic activity of tamoxifen metabolites in breast cancer.

show abstract

Tamoxifen and toremifene concentrations in plasma are greatly decreased by rifampin*

Abstract: Rifampin markedly reduces the plasma concentrations of tamoxifen and toremifene by inducing their CYP3A4-mediated metabolism. Concomitant use of rifampin or other potent inducers of CYP3A4 with tamoxifen and toremifene may reduce the efficacy of these antiestrogens.

Cited by 43 publications

References 15 publications

Comparative Metabolic Capabilities of CYP3A4, CYP3A5, and CYP3A7

Comparative Metabolic Capabilities of CYP3A4, CYP3A5, and CYP3A7

Comprehensive Evaluation of Tamoxifen Sequential Biotransformation by the Human Cytochrome P450 System in Vitro: Prominent Roles for CYP3A and CYP2D6

TGFβ2 and TβRII are valid molecular biomarkers for the antiproliferative effects of tamoxifen and tamoxifen metabolites in breast cancer cells

Contact Info

Product

Resources

About