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Decreased Serum Concentrations of Tamoxifen and Its Metabolites Induced by Aminoglutethimide1

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Decreased Serum Concentrations of Tamoxifen and Its Metabolites Induced by Aminoglutethimide1 (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 Aminoglutethimide inhibits the enzyme aromatase, which converts androgens to estrogens in peripheral fat tissue (3). The anticstrogen tamoxifen and the aromatase inhibitor aminoglute- This conversion is the main estrogen source in postmenopausal thimide show similar response rates when used in the endocrine manage women. In addition, aminoglutethimide may reduce the con ment of advanced breast cancer. However, numerous clinical trials have centration of plasma estrogens by enhancement of estrogen demonstrated no increase in response rate from treatment with the drug combination of tamoxifen plus aminoglutethimide. We investigated the metabolism (10, 11). Aminoglutethimide causes response rates possibility of a pharmacokinetic interaction between these two drugs in in postmenopausal breast cancer patients similar to those of six menopausa! woman with breast cancer. All patients were investigated tamoxifen, but because of more frequent side effects aminoglu under three different conditions (termed phases A, B, and C). The steady tethimide is generally used after tamoxifen as a second line state kinetics of tamoxifen were determined when administered alone endocrine treatment (12). (phase A) and after coadministration of aminoglutethimide for 6 weeks Combination therapy with tamoxifen plus aminoglutethi (phase B). In phase B, the pharmacokinetics for aminoglutethimide were mide should afford both estrogen receptor blockade and reduced determined and compared with these parameters after a tamoxifen wash plasma estrogen levels, and because of different targeting of out of 6 weeks (phase C). The serum concentration of tamoxifen and these drugs the combination is expected to be more effective most of its metabolites |[rrani-l(4-/8-hydroxy-ethoxyphenyl)-l,2-diphen- ylbut-l-ene|, 4-hydroxytamoxifen, 4-hydroxy-/V-desmethyltamoxifen, N- than monotherapy. This possibility is supported by studies on desmethyltamoxifen, and /V-desdimethyltamoxifen) were markedly re human breast carcinoma transplanted into nude mice (13), but the results from clinical trials have been disappointing (14-19) duced following aminoglutethimide administration, corresponding to an increase in tamoxifen clearance from 189-608 nil min. The amount of since they all show that the response to tamoxifen is not most metabolites in serum increased relative to the amount of parent augmented by adding aminoglutethimide (Table 1). tamoxifen. These data are consistent with induction of tamoxifen metab The reason why the response rate is not increased with olism during aminoglutethimide exposure. We found no effect of tamox combination therapy has not been evaluated. A pharmacoki ifen on aminoglutethimide pharmacokinetics or acetylation. We conclude netic interaction should be considered, especially because ami that this aminoglutethimide-tamoxifen interaction should be taken into noglutethimide is a potent inducer of certain hepatic mixed account when evaluating the clinical effect of this drug combination function oxidases and enhances the metabolism of several drugs relative to monotherapy. and steroids (10, 20,21 ). In addition, tamoxifen might influence the disposition of aminoglutethimide. Tamoxifen is a potent INTRODUCTION inhibitor of some mixed function oxidases in vitro (22) and may inhibit its own metabolism (23-25) as well as the metabolism The growth of human breast cancer is supported by endoge of other drugs (26-28). nous estrogens (1, 2). Tamoxifen and aminoglutethimide are In the present paper we describe the effect of aminoglutethi drugs currently used in the endocrine management of breast mide on the disposition of tamoxifen in patients receiving cancer, and they probably act by suppressing the growth-stim steady state tamoxifen treatment. We also report that tamoxifen ulating effect of estrogens (2-4). does not affect aminoglutethimide disposition. The investiga Tamoxifen [trans- l-(4-/i-dimethylaminoethoxyphenyl)-1,2- tion was motivated by the large number of clinical studies of diphenylbut-l-ene] is a nonsteroidal antiestrogen which is ef the combination therapy (Table 1) and also by preliminary fective against breast cancer in both pre- and postmenopausal findings suggesting that aminoglutethimide alters serum levels women. It is assumed to exert its main effects by blocking the of tamoxifen and its metabolites.1 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. MATERIALS AND METHODS Significant amounts of hydroxylated metabolites, including the Patients. All patients gave their informed consent to participate in primary alcohol, 4-hydroxytamoxifen, (4) and 4-hydroxy-jV- the study. Six postmenopausal women were enrolled. All of them had desmethyltamoxifen (5) have also been demonstrated in serum. advanced breast cancer relapsing during tamoxifen therapy and were, This may be important since some hydroxylated metabolites therefore, transferred to an aminoglutethimide regimen. Patient char have higher affinity in vitro toward the estrogen receptor than acteristics are given in Table 2. All patients had normal liver and renal the parent drug, tamoxifen (6-9). Thus, biotransformation of function tests. One patient (K. N.) did not enter the final part of the tamoxifen may be an important determinant of drug action. study (phase C) because of rapidly progressing disease. Known metabolites of tamoxifen formed through demethyla- Chemicals. Tamoxifen, metabolite B. and metabolite X were obtained tion and hydroxylation are depicted in Fig. 1. from Pharmachemie B.V. (Haarlem, Holland) and metabolites Y, BX, and Z were gifts from Imperial Chemical Industries, PLC, Pharmaceu Received 2/21/90; accepted 5/23/90. ticals Division (Macclesfield, United Kingdom). Aminoglutethimide The costs of publication of this article were defrayed in part by the payment and iV-acetylaminoglutethimide were gifts from Ciba-Geigy (Basel. 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. Switzerland). 1This work was supported by grants from the Norwegian Cancer Society and Study Protocol. The study protocol was approved by the regional the Torsteds legat. ethical committee. 2To whom requests for reprints should be addressed, at Department of Pharmacology and Toxicology. Armauer Hansens Hus, N-5021 Bergen. Norway. ' C. Rose and E. A. Lien, unpublished data. 5851 Downloaded from cancerres.aacrjournals.org on September 26, 2021. © 1990 American Association for Cancer Research. INTERACTION BETWEEN TAMOXIFEN AND AMINOGLUTETHIMIDK CH, CH, N - Glucuronide NCH,CH NCH2CH2 CH/ Glucuronide Tamoxifen MetaboliteB 4-Hydroxytamoxifen N - Glucuronide a i, CH,. Glucuronide S°-\_/ CH2CH3 Metabolite BX Metabolite X N -Desmethyltamoxifen 4-Hydroxy-N -desmethyltamoxifen Hydroxylated metabolites Excretory with high estrogen products of receptor affinity tamoxifen N - Glucuronide CH2CH3 Metabolite 7. N -Desdimethyltamoxifen Glucuronide Metabolite Y Primary alcohol Fig. I. Proposed metabolic pathways of tamoxifen. Table 1 Trials comparing lanw\ifen monotherapy with the combination of lamoxifen and aminoglutethimide in breast cancer patient* rateDrug"TAMTAM Response PR//"18/6023/623/94/115/266/2621/4925/5132/9424/8318/3411/29%303733361923434934295338Ref.141516171819+ (mg)lOb.i.d.lOb.i.d. AG 250q.i.d. 11TAMTAM 20b.i.d.lOb.i.d.lOb.i.d. AG 250 q.i.d. IITAMTAM 20b.i.d.10 b.i.d.lOb.i.d. AG 250 q.i.d. HTAMTAM 10b.i.d.lOb.i.d.lOb.i.d. ACIITAMTAM 250 q.i.d. 10+201010 + t.i.d.lOt.i.d. AG 250 q.i.d. HTAMTAM 20t.i.d.20 b.i.d.20 b.i.d. AG 250 q.i.d. HDose 10+10 + 20CR ' CR. complete response; PR. partial response: n. number of patients: TAM. tamoxifen: AG. aminoglutelhimide: H. hydrocortisone. 5852 Downloaded from cancerres.aacrjournals.org on September 26, 2021. © 1990 American Association for Cancer Research. INTERACTION BETWEEN TAMOXIFEN AND AMINOGLUTETHIMIDE Table 2 Palien! characteristics anil drug treatment through a quartz tube and then monitored by fluorescence detection Treatment (30). Tamoxifen"Age The within-day precision (CV) of the assay for tamoxifen and its metabolites Y. B, X. and Z were 0.6-5.6% for serum levels between 10 of and 800 ng/ml. Because our standard for metabolite BX is a mixture treatment of the cis and trans isomers (5), the CV was not determined for this before en Patient(yr)A. trance(mo)66 (mg)30 dose(mg)250q.i.d. metabolite. Determination of Aminoglutethimide and ¿Y-Acet)laminoglutethimide. K. 66 q.d. I. L. 60 30 30 q.d. 250 t.i.d. Serum was deproteinizcd using a mixture of acetonitrile and perchloric M. H. 60 41 20 q.d. 250q.i.d. acid. The samples were chromatographed on a 3-/jm ODS Hypersil B. H. 62 6 30 q.d. 250 q.i.d. column, which was eluted isocratically as described previously (31). K. N. 47 31 30 t.i.d. 250 q.i.d. The absorbance was routinely recorded at 242 nm. q.Ld.•M. F. 60Duration 18Dose 80 q.d.Aminoglutethimide*250 The CVs for aminoglutethimide and A'-acetylaminoglutethimide at Phases A and B. * Phases B and C. a concentration of 0.5 iig/ml are 3.9 and 2.6%, respectively. Identification of Metabolite BX by LC/MS. For patient K. N., all serum samples from phase A and all samples from phase B were pooled Tamoxifen and aminoglutethimide pharmacokinetics were evaluated in separate tubes. Ten ml from each pool was extracted with 10 volumes under three different conditions, termed phases A, B, and C. Drug of hexane/butanol (98/2, v/v). The supernatant was evaporated in doses are given in Table 2. plastic beakers at 55°Cunder nitrogen, redissolved in 1 ml 50% aceto Phase A refers to chronic (>6 months) treatment with tamoxifen nitrile.
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