Paired-ion chromatographic analysis of tamoxifen and two major metabolites in plasma

Golander, Yechiel; Sternson, Larry A.

doi:10.1016/s0378-4347(00)81267-0

Cited by 68 publications

(12 citation statements)

References 5 publications

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“…Subsequent improvements were made [90] but the method significantly underestimated phenolic metabolites (4-hydroxytamoxifen) and had no internal standardization. In contrast, a method of post column fluorescence activation [91] or preliminary purification from interfering substance using a Sep-Pack C18 cartridge (Waters Association, Milford MA) [92] with internal standardization considerably improved accuracy.…”

Section: Clinical Pharmacologymentioning

confidence: 99%

New insights into the metabolism of tamoxifen and its role in the treatment and prevention of breast cancer

2007

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The metabolism of tamoxifen is being redefined in the light of several important pharmacological observations. Recent studies have identified 4-hydroxy N-desmethyl tamoxifen (endoxifen) as an important metabolite of tamoxifen necessary for antitumor actions. The metabolite is formed through the enzymatic product of CYP2D6 which also interacts with specific selective serotonin reuptake inhibitors (SSRIs) used to prevent the hot flashes observed in up to 45% of patients taking tamoxifen. Additionally, the finding that enzyme variants of CYP2D6 do not promote the metabolism of tamoxifen to endoxifen means that significant numbers of women might not receive optimal benefit from tamoxifen treatment. Clearly these are particularly important issues not only for breast cancer treatment but also for selecting premenopausal women, at high risk for breast cancer, as candidates for chemoprevention using tamoxifen.

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Section: Clinical Pharmacologymentioning

confidence: 99%

New insights into the metabolism of tamoxifen and its role in the treatment and prevention of breast cancer

2007

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“…Recently, we validated a new and improved HPLC method for the assay of tamoxifen and its metabolites (Brown, Bain and Jordan, in preparation). Unlike the published HPLC methods (75,76) that have no internal standard and convert triphenylethylenes to phenanthrenes before chromato- graphy, our methodology uses ICI 99,311 or Metabolite E (depending upon the column used to detect different metabolites) as internal standards and post-column UV activation and fluorescence detection. Although we have identified new metabolites with this methodology (see later), there is no doubt that glc/ms is the most specific assay method (79).…”

Section: Detection Of Metabolitesmentioning

confidence: 99%

Metabolites of tamoxifen in animals and man: Identification, pharmacology, and significance

Jordan

Chem

1982

Breast Cancer Res Tr

128

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Over the past decade, the non-steroidal antiestrogen tamoxifen has gained general acceptance for the palliative treatment of breast cancer. Although there has been much interest in the pharmacology of tamoxifen, our knowledge of its metabolism in laboratory animals and patients is incomplete and the precise mechanism of action within target tissue and breast tumor cells is unknown. This review briefly describes the pharmacology of tamoxifen in various laboratory species and patients. Several metabolites of tamoxifen are known and their relative potencies as estrogens and antiestrogens are compared with the parent compound. Apart from monohydroxytamoxifen, none of tamoxifen's metabolites are more potent antiestrogens, but a metabolite in the dog, Metabolite E, is fully estrogenic. Routine assays (tlc, HPLC, glc/ms) are available to detect tamoxifen, N-desmethyltamoxifen, monohydroxytamoxifen, and a newly identified metabolite, designated Metabolite Y, in biological fluids. Continuous therapy with tamoxifen (10 mg bid) produces steady-state levels (100-200 ng/ml serum) within 4 weeks. Levels of N-desmethyltamoxifen are often up to twice the levels achieved with tamoxifen, while levels of monohydroxytamoxifen and Metabolite Y are below 10 ng/ml. Although monohydroxytamoxifen has a high binding affinity for the estrogen receptor, the metabolic activation of tamoxifen is an advantage rather than a requirement for antiestrogenic activity. The action of tamoxifen in vivo is the net result of the individual actions of the parent compound and its metabolites competing for the occupation of receptors within target tissues and tumors.

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“…Organic extraction Diethyl ether (Golander & Sternson, 1980); hexane-butanol 2% . Plasma (0.5 ml), spiked with 2 jg clomifene, was extracted twice with 4 vol of organic solvant each time.…”

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confidence: 99%

Optimised analysis of tamoxifen and its main metabolites in the plasma and cytosol of mammary tumours

Milano¹,

Etienne²,

Frénay³

et al. 1987

Br J Cancer

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Centre Antoine Lacassagne, 36 voie Romaine, 06054 Nice Cedex, France Summary Recent biochemical and pharmacological findings concerning tamoxifen (TMX) have proven that both the unchanged drug and the main metabolites, N-desmethyltamoxifen (NDT) and 4-hydroxytamoxifen (4 OHT) are biologically active. An HPLC method based on on-line post-column UV irradiation with fluorescence detection is described. Optimized conditions allowed complete and rapid separation of TMX 40HT, NDT and two other recently reported metabolites, Y and Z. This method was applied to plasma and cytosol drug and metabolite analyses. In plasma, from the moment of initial drug administration until the steady state (after 1 month or more of continuous oral TMX treatment), the values of NDT to TMX ratios were completely reversed: 22 to 215 in mean %, P<0.01. The presence of metabolites Y and Z is significant. 40HT, hardly detectable at the first dose, was measured at the steady state with high interpatient variability. It is hypothesized that metabolite evolution with time may be due to auto-induction of drug metabolism. In cytosols, which were all obtained during continuous TMX treatment, the ratios between TMX and metabolites were comparable to those observed in plasma, but with greater interpatient variability. Metabolite Y was not detectable in cytosols. This variability was not linked to the levels of cytosolic oestradiol receptors before initiation of treatment.

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Paired-ion chromatographic analysis of tamoxifen and two major metabolites in plasma

Cited by 68 publications

References 5 publications

New insights into the metabolism of tamoxifen and its role in the treatment and prevention of breast cancer

New insights into the metabolism of tamoxifen and its role in the treatment and prevention of breast cancer

Metabolites of tamoxifen in animals and man: Identification, pharmacology, and significance

Optimised analysis of tamoxifen and its main metabolites in the plasma and cytosol of mammary tumours

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