The metabolism of razoxane and dexrazoxane in the Sprague-Dawley rat
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Date
1998-05-01T00:00:00Z
Authors
Aoyama, Ronald G.
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Abstract
The objectives of this project were to use a rat model to study the stereoselective metabolism of razoxane and the metabolism of dexrazoxane to its intermediate hydrolysis products. A solid phase method for extraction of razoxane from plasma and a chiral HPLC method for the simultaneous quantitation of razoxane enantiomers, were developed. These methods were then used to study the stereoselective metabolism of razoxane in a rat model after i.v. administration. In order to follow the plasma concentrations of the dexrazoxane hydrolysis intermediate products, attempts were made to derivatize dexrazoxane and its hydrolysis intermediates with the fluorescent label 2-bromomethyl-4,5-diphenyloxazole. An HPLC method was used to analyze these fluorescent derivatives. Dexrazoxane was successfully derivatized with the oxazole but the fluorescent derivatives of the hydrolysis intermediates were unable to be identified. This approach was abandoned. Several methods were evaluated for their ability to separate dexrazoxaneand the hydrolysis intermediates from buffer and rat plasma. A simple acetonitrile plasma protein precipitation step gave good recoveries of dexrazoxane and its hydrolysis intermediates from rat plasma. An HPLC method was then designed to separate dexrazoxane and its hydrolysis intermediates in rat plasma samples. Post-column derivatization of dexrazoxane and its hydrolysis intermediates with NaOH solution in a reaction bed and detection by UV absorption gave reasonable sensitivities while reducing interferences from endogenous materials in the rat plasma.