Effect of tamoxifen pretreatment on the pharmacokinetics, metabolism and cardiotoxicity of doxorubicin in female rats.

Abstract

The purpose of this study was to examine the effect of tamoxifen pretreatment on the metabolism and pharmacokinetics of doxorubicin. We tested the hypothesis that the pretreatment would counteract the side effects of doxorubicin and modify the disposition of the drug. The concentration-time profiles 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 following a 10-day tamoxifen pretreatment at a dose of 1 mg/kg per day. Furthermore, under the same experimental protocol the serum concentration-time profile of endothelin was determined as a biomarker of toxicity. 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 14C-doxorubicin (specific activity 0.4 microCi/mg, 10 mg/kg) intravenously. Plasma, blood cells, bile and urine were collected periodically and analyzed for doxorubicin and its metabolites. 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 effect of tamoxifen on the in vitro metabolism of doxorubicin by the cytosolic enzyme aldo-keto reductase. Tamoxifen pretreatment reduced the total protein of the cytosolic fraction by 50% and reduced the formation of doxorubicinol both in vitro and in vivo. The pretreatment resulted in a notable increase in the area under plasma and blood cells concentration-time curves of doxorubicin and a significant reduction in mean residence time, apparent volume of distribution and serum endothelin levels. We attributed the increase in the area under the curves of plasma and blood cells following tamoxifen pretreatment to a reduction in the uptake of doxorubicin by peripheral tissues. This conclusion was consistent with the reduction in the volume of distribution of plasma, mean residence time and higher availability of the parent compound for excretion. 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 tamoxifen, in addition to being a modulator of P-glycoprotein and counteracting the effects of doxorubicin at the cellular level, also alters the metabolic profile of doxorubicin either by inhibiting the formation of the toxic metabolite doxorubicinol or by reducing the enzyme responsible for the biotransformation. The change in metabolism may well be a contributing factor to reduction of serum endothelin levels.