Lien E A, Anker G, Lønning P E, Solheim E, Ueland P M
Department of Pharmacology and Toxicology, University of Bergen, Norway.
Cancer Res. 1990 Sep 15;50(18):5851-7.
The antiestrogen tamoxifen and the aromatase inhibitor aminoglutethimide show similar response rates when used in the endocrine management of advanced breast cancer. However, numerous clinical trials have demonstrated no increase in response rate from treatment with the drug combination of tamoxifen plus aminoglutethimide. We investigated the possibility of a pharmacokinetic interaction between these two drugs in six menopausal woman with breast cancer. All patients were investigated under three different conditions (termed phases A, B, and C). The steady state kinetics of tamoxifen were determined when administered alone (phase A) and after coadministration of aminoglutethimide for 6 weeks (phase B). In phase B, the pharmacokinetics for aminoglutethimide were determined and compared with these parameters after a tamoxifen washout of 6 weeks (phase C). The serum concentration of tamoxifen and most of its metabolites ([trans-1(4-beta-hydroxy-ethoxyphenyl)-1,2-diphenylbut-1-ene], 4-hydroxytamoxifen, 4-hydroxy-N-desmethyltamoxifen, N-desmethyltamoxifen, and N-desdimethyltamoxifen) were markedly reduced following aminoglutethimide administration, corresponding to an increase in tamoxifen clearance from 189-608 ml/min. The amount of most metabolites in serum increased relative to the amount of parent tamoxifen. These data are consistent with induction of tamoxifen metabolism during aminoglutethimide exposure. We found no effect of tamoxifen on aminoglutethimide pharmacokinetics or acetylation. We conclude that this aminoglutethimide-tamoxifen interaction should be taken into account when evaluating the clinical effect of this drug combination relative to monotherapy.
抗雌激素药物他莫昔芬和芳香化酶抑制剂氨鲁米特在晚期乳腺癌的内分泌治疗中显示出相似的缓解率。然而，大量临床试验表明，他莫昔芬与氨鲁米特联合用药并未提高缓解率。我们研究了这两种药物在6名绝经后乳腺癌女性中发生药代动力学相互作用的可能性。所有患者在三种不同条件下（称为A、B和C期）接受研究。单独给予他莫昔芬时（A期）以及联合给予氨鲁米特6周后（B期），测定他莫昔芬的稳态动力学。在B期，测定氨鲁米特的药代动力学，并与他莫昔芬洗脱6周后的这些参数进行比较（C期）。给予氨鲁米特后，他莫昔芬及其大部分代谢产物（[反式-1(4-β-羟基乙氧基苯基)-1,2-二苯基丁-1-烯]、4-羟基他莫昔芬、4-羟基-N-去甲基他莫昔芬、N-去甲基他莫昔芬和N-去二甲基他莫昔芬）的血清浓度显著降低，这对应于他莫昔芬清除率从189 - 608 ml/分钟增加。血清中大多数代谢产物的量相对于母体他莫昔芬的量增加。这些数据与氨鲁米特暴露期间他莫昔芬代谢的诱导一致。我们发现他莫昔芬对氨鲁米特的药代动力学或乙酰化没有影响。我们得出结论，在评估这种联合用药相对于单一疗法的临床效果时，应考虑这种氨鲁米特 - 他莫昔芬相互作用。
