(CANCER RESEARCH 50. 5851-5857. September 15. 1990) Decreased Serum Concentrations of Tamoxifen and Its Metabolites Induced by Aminoglutethimide1 Ernst A. Lien,2 Gun Anker, Per Eystein Lgnning, Einar Solheim, and Per M. Ueland Department i>j 'Pharmacology and Toxicology [E. A. I... E. S]; Clinical Pharmacology I nit. Department of Pharmacology and Toxicology /P. M. l './; and Department of Oncology I(i. A., P. fi. Lj, L'niversity of Bergen, .\-502l, Bergen, \onvay ABSTRACT The anticstrogen tamoxifen and the aromatase inhibitor aminoglute- thimide show similar response rates when used in the endocrine manage ment 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 menopausa! 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 wash out of 6 weeks (phase C). The serum concentration of tamoxifen and most of its metabolites |[rrani-l(4-/8-hydroxy-ethoxyphenyl)-l,2-diphen- ylbut-l-ene|, 4-hydroxytamoxifen, 4-hydroxy-/V-desmethyltamoxifen, N- desmethyltamoxifen, and /V-desdimethyltamoxifen) were markedly re duced following aminoglutethimide administration, corresponding to an increase in tamoxifen clearance from 189-608 nil min. The amount of most metabolites in serum increased relative to the amount of parent tamoxifen. These data are consistent with induction of tamoxifen metab olism during aminoglutethimide exposure. We found no effect of tamox ifen 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. INTRODUCTION The growth of human breast cancer is supported by endoge nous estrogens (1, 2). Tamoxifen and aminoglutethimide are drugs currently used in the endocrine management of breast cancer, and they probably act by suppressing the growth-stim ulating effect of estrogens (2-4). Tamoxifen [trans- l-(4-/i-dimethylaminoethoxyphenyl)-1,2- diphenylbut-l-ene] is a nonsteroidal antiestrogen which is ef fective against breast cancer in both pre- and postmenopausal women. It is assumed to exert its main effects by blocking the action of estrogens at the receptor site (4). Tamoxifen under goes extensive hepatic metabolism, and in man metabolites formed by /V-demethylation are the main circulating species. Significant amounts of hydroxylated metabolites, including the primary alcohol, 4-hydroxytamoxifen, (4) and 4-hydroxy-jV- desmethyltamoxifen (5) have also been demonstrated in serum. This may be important since some hydroxylated metabolites have higher affinity in vitro toward the estrogen receptor than the parent drug, tamoxifen (6-9). Thus, biotransformation of tamoxifen may be an important determinant of drug action. Known metabolites of tamoxifen formed through demethyla- tion and hydroxylation are depicted in Fig. 1. Received 2/21/90; accepted 5/23/90. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C'. Section 1734 solely to indicate this fact. 1This work was supported by grants from the Norwegian Cancer Society and the Torsteds legat. 2To whom requests for reprints should be addressed, at Department of Pharmacology and Toxicology. Armauer Hansens Hus, N-5021 Bergen. Norway. Aminoglutethimide inhibits the enzyme aromatase, which converts androgens to estrogens in peripheral fat tissue (3). This conversion is the main estrogen source in postmenopausal women. In addition, aminoglutethimide may reduce the con centration of plasma estrogens by enhancement of estrogen metabolism (10, 11). Aminoglutethimide causes response rates in postmenopausal breast cancer patients similar to those of tamoxifen, but because of more frequent side effects aminoglu tethimide is generally used after tamoxifen as a second line endocrine treatment (12). Combination therapy with tamoxifen plus aminoglutethi mide should afford both estrogen receptor blockade and reduced plasma estrogen levels, and because of different targeting of these drugs the combination is expected to be more effective than monotherapy. This possibility is supported by studies on human breast carcinoma transplanted into nude mice (13), but the results from clinical trials have been disappointing (14-19) since they all show that the response to tamoxifen is not augmented by adding aminoglutethimide (Table 1). The reason why the response rate is not increased with combination therapy has not been evaluated. A pharmacoki netic interaction should be considered, especially because ami noglutethimide is a potent inducer of certain hepatic mixed function oxidases and enhances the metabolism of several drugs and steroids ( 10, 20,21 ). In addition, tamoxifen might influence the disposition of aminoglutethimide. Tamoxifen is a potent inhibitor of some mixed function oxidases in vitro (22) and may inhibit its own metabolism (23-25) as well as the metabolism of other drugs (26-28). In the present paper we describe the effect of aminoglutethi mide on the disposition of tamoxifen in patients receiving steady state tamoxifen treatment. We also report that tamoxifen does not affect aminoglutethimide disposition. The investiga tion was motivated by the large number of clinical studies of the combination therapy (Table 1) and also by preliminary findings suggesting that aminoglutethimide alters serum levels of tamoxifen and its metabolites.1 MATERIALS AND METHODS Patients. All patients gave their informed consent to participate in the study. Six postmenopausal women were enrolled. All of them had advanced breast cancer relapsing during tamoxifen therapy and were, therefore, transferred to an aminoglutethimide regimen. Patient char acteristics are given in Table 2. All patients had normal liver and renal function tests. One patient (K. N.) did not enter the final part of the study (phase C) because of rapidly progressing disease. Chemicals. Tamoxifen, metabolite B. and metabolite X were obtained from Pharmachemie B.V. (Haarlem, Holland) and metabolites Y, BX, and Z were gifts from Imperial Chemical Industries, PLC, Pharmaceu ticals Division (Macclesfield, United Kingdom). Aminoglutethimide and iV-acetylaminoglutethimide were gifts from Ciba-Geigy (Basel. Switzerland). Study Protocol. The study protocol was approved by the regional ethical committee. ' C. Rose and E. A. Lien, unpublished data. 5851 Research. on August 26, 2015. © 1990 American Association for Cancer cancerres.aacrjournals.org Downloaded from