effect of tamoxifen pretreatment on the pharmacokinetics, metabolism and cardiotoxicity of...

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ORIGINAL ARTICLE Sujata Vaidyanathan á Mehdi Boroujerdi Effect of tamoxifen pretreatment on the pharmacokinetics, metabolism and cardiotoxicity of doxorubicin in female rats Received: 2 September 1999 / Accepted: 14 April 2000 Abstract The purpose of this study was to examine the eect of tamoxifen pretreatment on the metabolism and pharmacokinetics of doxorubicin. We tested the hy- pothesis that the pretreatment would counteract the side eects of doxorubicin and modify the disposition of the drug. The concentration-time pro®les of doxorubicin in plasma and blood cells were determined in conjunction with the cumulative amount of renal and hepatobiliary elimination of unchanged drug and metabolites follow- ing a 10-day tamoxifen pretreatment at a dose of 1 mg/ kg per day. Furthermore, under the same experimental protocol the serum concentration-time pro®le of end- othelin was determined as a biomarker of toxicity. Methods: Female Sprague Dawley rats 225±275 g), pretreated orally for 10 days with corn oil or tamoxifen in corn oil 1 mg/kg per day), received 14 C-doxorubicin speci®c activity 0.4 lCi/mg, 10 mg/kg) intravenously. Plasma, blood cells, bile and urine were collected peri- odically and analyzed for doxorubicin and its metabo- lites. Four other groups of animals received the same pretreatment and non-labeled doxorubicin. Their serum samples were analyzed for endothelin. Two additional groups were also used to examine the eect of tamoxifen on the in vitro metabolism of doxorubicin by the cyto- solic enzyme aldo-keto reductase. Results: Tamoxifen pretreatment reduced the total protein of the cytosolic fraction by 50% and reduced the formation of doxoru- bicinol both in vitro and in vivo. The pretreatment re- sulted in a notable increase in the area under plasma and blood cells concentration-time curves of doxorubicin and a signi®cant reduction in mean residence time, apparent volume of distribution and serum endothelin levels. Conclusions: We attributed the increase in the area under the curves of plasma and blood cells fol- lowing tamoxifen pretreatment to a reduction in the uptake of doxorubicin by peripheral tissues. This con- clusion was consistent with the reduction in the volume of distribution of plasma, mean residence time and higher availability of the parent compound for excre- tion. An interesting observation was that the increase in concentration of doxorubicin in plasma was not concomitant with an increase in concentration of doxorubicinol. The levels of this toxic metabolite and its corresponding biliary rate constant were reduced by approximately 50%. The results demonstrate that tam- oxifen, in addition to being a modulator of P-glyco- protein and counteracting the eects of doxorubicin at the cellular level, also alters the metabolic pro®le of doxorubicin either by inhibiting the formation of the toxic metabolite doxorubicinol or by reducing the en- zyme responsible for the biotransformation. The change in metabolism may well be a contributing factor to reduction of serum endothelin levels. Key words Tamoxifen á Doxorubicin á Pharmacokinetics á Doxorubicinol á Endothelin Introduction Tamoxifen, a synthetic nonsteroidal antiestrogen, in addition to its application in treatment and prevention of breast cancer, is also a modulator of multidrug re- sistance and an antioxidant [7, 8, 15]. This compound and its major metabolite, 4-hydroxytamoxifen, are known to inhibit both metal ion-dependent enzymatic and nonenzymatic lipid peroxidation in a number of model membranes [22, 28, 29]. It has been reported that both the parent compound and its metabolite induce enzymes such as glutathione peroxidase, catalase and superoxide dismutase in postmenopausal women [22]. Cancer Chemother Pharmacol 2000) 46: 185±192 Ó Springer-Verlag 2000 S. Vaidyanathan 1 á M. Boroujerdi &) Department of Pharmaceutical Sciences, 206 Mugar Life Sciences Building, Northeastern University, Boston, MA 02115, USA e-mail: [email protected] Tel.: +1-617-3733091; Fax: +1-617-3738886 Present Address: 1 Biogen Inc., Preclinical Development, 14 Cambridge Center, Cambridge, MA 02142, USA

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Page 1: Effect of tamoxifen pretreatment on the pharmacokinetics, metabolism and cardiotoxicity of doxorubicin in female rats

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Page 2: Effect of tamoxifen pretreatment on the pharmacokinetics, metabolism and cardiotoxicity of doxorubicin in female rats

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