Serum and urine levels of tamoxifen and its metabolites in patients with advanced breast cancer after a loading dose and at steady-state levels

Vos, Dick de; Slee, P. H. Th. J.; Briggs, Ray J.; Stevenson, D.

doi:10.1007/s002800050854

Cited by 9 publications

(7 citation statements)

References 8 publications

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“… * 1 Mean demographic data taken from the literature (Fabian et al, 1981; Bratherton et al, 1984; Soininen et al, 1986; De Vos et al, 1992, 1998; Johnston et al, 1993; Buzdar et al, 1994; Lien et al, 1995; Peyrade et al, 1996; Dowsett et al, 1999, 2001; Guerrieri-Gonzaga et al, 2001; Decensi et al, 2003; Gallicchio et al, 2004; Kisanga et al, 2004; Hutson et al, 2005; Jin et al, 2005; Borges et al, 2006; Gjerde et al, 2008, 2010) . * 2 An intestinal transit time of 24 h was integrated into the PBPK-model of oral dosing tamoxifen to female breast cancer patients in order to take into account absorption of the substance additionally from distal segments of the intestine as indicated by the data and further discussed in the text .…”

Section: Resultsmentioning

confidence: 99%

Physiologically based pharmacokinetic modeling of tamoxifen and its metabolites in women of different CYP2D6 phenotypes provides new insight into the tamoxifen mass balance

et al. 2012

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Tamoxifen is a first-line endocrine agent in the mechanism-based treatment of estrogen receptor positive (ER+) mammary carcinoma and applied to breast cancer patients all over the world. Endoxifen is a secondary and highly active metabolite of tamoxifen that is formed among others by the polymorphic cytochrome P450 2D6 (CYP2D6). It is widely accepted that CYP2D6 poor metabolizers exert a pronounced decrease in endoxifen steady-state plasma concentrations compared to CYP2D6 extensive metabolizers. Nevertheless, an in-depth understanding of the chain of cause and effect between CYP2D6 genotype, endoxifen steady-state plasma concentration, and subsequent tamoxifen treatment benefit still remains to be evolved. In this study, physiologically based pharmacokinetic (PBPK)-modeling was applied to mechanistically investigate the impact of CYP2D6 phenotype on endoxifen formation in female breast cancer patients undergoing tamoxifen therapy. A PBPK-model of tamoxifen and its pharmacologically important metabolites N-desmethyltamoxifen (NDM-TAM), 4-hydroxytamoxifen (4-OH-TAM), and endoxifen was developed and validated. This model is able to simulate the pharmacokinetics (PK) after single and repeated oral tamoxifen doses in female breast cancer patients in dependence of the CYP2D6 phenotype. A detailed model-based analysis of the mass balance offered support for a recent hypothesis stating a more prominent role for endoxifen formation from 4-OH-TAM. In the future this model provides a good basis to further investigate the linkage of PK, mode of action, and treatment outcome in dependence of factors such as phenotype, ethnicity, or co-treatment with CYP2D6 inhibitors.

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Section: Resultsmentioning

confidence: 99%

Physiologically based pharmacokinetic modeling of tamoxifen and its metabolites in women of different CYP2D6 phenotypes provides new insight into the tamoxifen mass balance

et al. 2012

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“…Considering conformational isomers, hydroxylation positions (in both the alkene moiety or the three benzyl groups at different sites) and even N ‐oxidation, there are many different possibilities that are consistent with the formation of such large amount of isomers. Various studies have reported on the presence of these isomers in both plasma and urine (Teunissen et al ., ; Li et al ., ; De Vos et al ., ; Mazzarino et al ., , , ; Lu et al ., ; Dahmane et al ., ). Similarly to mono‐hydroxylated metabolites, it was not possible to find characteristic fragmentation to figure out the different isomers and their detailed structure.…”

Section: Resultsmentioning

confidence: 99%

“…While TMX metabolism studies have been reported extensively in serum (Gjerde et al ., ; Teunissen et al ., , , ), plasma (Stearns et al ., ; Murphy et al ., ; Stevenson et al ., ; Kikuta and Schmid, ; Dahmane et al ., ; Jaremko et al ., ) and other specimens such as tumoral tissues (Murphy et al ., ; MacCallum et al ., ), in vitro preparations using liver microsomes (Jones et al . ; Lu et al ., ; Lim et al ., ) and synthetic gastric acids (Li et al ., ), the urinary excretion of TMX metabolites has not been studied in such detail (De Vos et al ., ; Mazzarino et al ., , , ; Lu et al ., ).…”

Section: Introductionmentioning

confidence: 99%

“…Various authors have reported on the metabolism of TMX, as recently reviewed by Beijnen and co-workers (Teunissen et al, 2010). While TMX metabolism studies have been reported extensively in serum (Gjerde et al, 2005;Teunissen et al, 2009Teunissen et al, , 2011aTeunissen et al, , 2011b, plasma (Stearns et al, 2003;Murphy et al, 1987a;Stevenson et al, 1988;Kikuta and Schmid, 1989;Dahmane et al, 2010;Jaremko et al, 2010) and other specimens such as tumoral tissues (Murphy et al, 1987b;MacCallum et al, 1997), in vitro preparations using liver microsomes (Jones et al 1996;Lu et al, 1996;Lim et al, 1997) and synthetic gastric acids (Li et al, 2001), the urinary excretion of TMX metabolites has not been studied in such detail (De Vos et al, 1998;Mazzarino et al, 2008Mazzarino et al, , 2010Mazzarino et al, , 2013Lu et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

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Study of tamoxifen urinary metabolites in rat by ultra‐high‐performance liquid chromatography time‐of‐flight mass spectrometry

Domínguez-Romero

García-Reyes

Beneito‐Cambra

et al. 2015

Biomedical Chromatography

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Tamoxifen (TMX) is a nonsteroidal estrogen antagonist drug used for the treatment of breast cancer. It is also included in the list of banned substances of the World Anti Doping Agency (WADA) prohibited in and out of competition. In this work, the excretion of urinary metabolites of TMX after a single therapeutic dose administration in rats has been studied using ultra-high-performance liquid chromatography electrospray time-of-flight mass spectrometry (UHPLC-TOFMS). A systematic strategy based on the search of typical biotransformations that a xenobiotic can undergo in living organisms, based on their corresponding molecular formula modification and accurate mass shifts, was applied for the identification of TMX metabolites. Prior to UHPLC-TOFMS analyses, a solid-phase extraction step with polymeric cartridges was applied to urine samples. Up to 38 TMX metabolites were detected. Additional collision induced dissociation (CID) MS/MS fragmentation was performed using UHPLC-QTOFMS. Compared with recent previous studies in human urine and plasma, new metabolites have been reported for the first time in urine. Metabolites identified in rat urine include the oxygen addition, owing to different possibilities for the hydroxylation of the rings in different positions (m/z 388.2271), the incorporation of two oxygen atoms (m/z 404.2220) (including dihydroxylated derivatives or alternatives such as epoxidation plus hydroxylation or N-oxidation and hydroxylation), epoxide formation or hydroxylation and dehydrogenation [m/z 386.2114 (+O -H2 )], hydroxylation of the ring accompanied by N-desmethylation (m/z 374.2115), combined hydroxylation and methoxylation (m/z 418.2377), desaturated TMX derivate (m/z 370.2165) and its N-desmethylated derivate (m/z 356.2009), the two latter modifications not previously being reported in urine. These findings confirm the usefulness of the proposed approach based on UHPLC-TOFMS.

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“…In the report of Reddel and Sutherland, 12 based on T47D human mammary cancer cells, 10 −11 M was a noeffect dose for tamoxifen, stimulation of colony formation was seen at 10 −10 to 10 −8 M, and clear growth suppression occurred at 10 −5 M. Values at 10 −7 and 10 −6 M were approaching baseline. Steady-state serum levels of chronic-treatment tamoxifen in breast cancer patients were 2-4 × 10 −7 M. 13 In a protocol where high-dose tamoxifen was combined with cisplatin, targeting lung cancer, serum levels were 4-8 × 10 −6 M. 14 So tamoxifen, like suramin, is found clinically at serum concentrations falling between levels that were clearly stimulatory and those that were definitely inhibitory for the cultured cells. Further study of this hormetic balance is clearly needed, both in vivo and in cell culture.…”

Section: How Relevant Are the Hormetic Doses?mentioning

confidence: 98%

Cancer Biology and Hormesis: Comments on Calabrese (2005)

Anderson

2005

Critical Reviews in Toxicology

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Large numbers of chemicals of a variety of types exhibit apparent hormetic effects on cultured human cancer cells, causing stimulation of cell growth or related changes at low doses, followed by inhibition at higher doses. Many of the studies listed are not fully convincing, due to lack of appropriate controls or sufficient number of doses. However, the proposed hormetic response seems firmly established in a subset of these experiments. Significance with regard to in vivo cancer growth has not been pursued and must be a priority for the future. For several examples where in vivo titers are known, such as, resveratrol, suramin, and tamoxifen, comparison of the dose and concentration ranges confirms that hormesis could be an issue in vivo. Further investigations are warranted, especially for therapeutic drugs, phytochemicals, and environmental toxicants.

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Serum and urine levels of tamoxifen and its metabolites in patients with advanced breast cancer after a loading dose and at steady-state levels

Cited by 9 publications

References 8 publications

Physiologically based pharmacokinetic modeling of tamoxifen and its metabolites in women of different CYP2D6 phenotypes provides new insight into the tamoxifen mass balance

Physiologically based pharmacokinetic modeling of tamoxifen and its metabolites in women of different CYP2D6 phenotypes provides new insight into the tamoxifen mass balance

Study of tamoxifen urinary metabolites in rat by ultra‐high‐performance liquid chromatography time‐of‐flight mass spectrometry

Cancer Biology and Hormesis: Comments on Calabrese (2005)

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