Dec. 2, 2003-根據一項發表於12月3日國家癌症研究院期刊的前瞻性試驗結果顯示,選擇性血清素再吸收抑制劑(SSRIs)可能會減低tamoxifen的效果。
  現為美國馬里蘭州巴爾的摩港市Johns Hopkins大學的Vered Stearns博士和同事表示,選擇性雌激素受體調節者Tamoxifen,能被cytochrome P450 (CYP)酵素轉換為4-hydroxy-tamoxifen和其他的活性代謝物,SSRIs常被開作處方以減輕與tamoxifen有關的熱潮紅症狀,它能抑制CYPs。
  Endoxifen是以前未被確認的一種tamoxifen活性代謝物,其血漿中的濃度從接受paroxetine前的12.4ng/mL降到paroxetine治療後的5.5ng/mL (P = .004),而血漿中的4-hydroxy-tamoxifen濃度則不因paroxetine療法而降低。具有CYP2D6基因型的婦女其Endoxifen的濃度減少了64%,但是CYP2D6基因型變體的婦女僅減少了24%。
  在一項支持性社論中,美國明尼蘇達州Mayo 診所的Matthew P. Goetz醫師和Charles L. Loprinzi醫師贊同以上的結論,他們指出由於SSRIs不同於CYP2D6抑制的濃度,他們與tamoxifen之間的相互作用必須更進一步的研究。

Selective Serotonin Reuptake I

By Laurie Barclay, MD
Medscape Medical News

Dec. 2, 2003 — Selective serotonin reuptake inhibitors (SSRIs) may reduce tamoxifen efficacy, according to the results of a prospective trial published in the Dec. 3 issue of the Journal of the National Cancer Institute. Although these antidepressants inhibit the enzyme that converts tamoxifen to its active metabolites, the authors and editorialists suggest that more study is needed before changing recommendations for their use.

"Tamoxifen, a selective estrogen receptor modulator, is converted to 4-hydroxy-tamoxifen and other active metabolites by cytochrome P450 (CYP) enzymes," write Vered Stearns, MD, now at Johns Hopkins University in Baltimore, Maryland, and colleagues. "SSRIs, which are often prescribed to alleviate tamoxifen-associated hot flashes, can inhibit CYPs."

In this study, 12 women with breast cancer were given paroxetine, which inhibits CYP2D6, for four weeks during their standard course of adjuvant tamoxifen therapy.

Plasma concentrations of endoxifen, a previously unrecognized active metabolite of tamoxifen, were reduced from 12.4 ng/mL before paroxetine administration to 5.5 ng/mL after paroxetine treatment (P = .004), whereas plasma concentrations of 4-hydroxy-tamoxifen were not reduced by paroxetine treatment. Endoxifen concentrations decreased by 64% in women with a wild type CYP2D6 genotype but by only 24% in women with a variant CYP2D6 genotype (P = .03).

The authors note that these findings "raise the possibility that pharmacogenetic variation in CYP2D6 activity may influence therapeutic outcomes from tamoxifen treatment.... Larger trials are required to evaluate the clinical implications of low circulating endoxifen concentrations and, until further data become available, the results of this small study should not alter treatment recommendations."

GlaxoSmithKline helped support this study and its investigators.

In an accompanying editorial, Matthew P. Goetz, MD, and Charles L. Loprinzi, MD, from the Mayo Clinic in Rochester, Minnesota, agree with the above conclusion. They point out that because SSRIs differ in their levels of CYP2D6 inhibition, their interaction with tamoxifen needs to be studied further.

Future research "will help to clarify whether the CYP2D6 genotype, as well as variation in multiple different genes involved in the uptake, distribution, and metabolism of tamoxifen, will affect the important clinical outcomes associated with tamoxifen," they write. "It is clear that the results of these studies continue to move us toward a time when ready access to gene sequence information, when used properly, will improve the ability of health care professionals to individualize therapy."

J Natl Cancer Inst. 2003;95:1734-1735, 1758-1764

Reviewed by Gary D. Vogin, MD

2016/10/12 下午 04:04:37
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