Clinical pharmacology of dexrazoxane

Abstract

Dexrazoxane is a synthetic bisdiketopiperazine two-ringed compound which hydrolyzes to an EDTA analog. These rings undergo intracellular hydrolysis to form the single and double (ICRF-198) chelating forms of the compound by both enzymatic and non-enzymatic catalysis. These dexrazoxane metabolites are efficient at stripping the cations from the iron:anthracycline complex. The disruption of the complex prevents the oxidative damage from free radicals promoted by this anthracycline complex. Pharmacologic studies of single agent dexrazoxane (originally studied as an antineoplastic agent) demonstrates an alpha half-life of approximately 30 minutes and a beta half-life of 2 to 4 hours. When given in combination with anthracyclines (e.g. doxorubicin or epirubicin) the pharmacokinetics of dexrazoxane are unchanged. Additional studies of anthracycline metabolism when given in combination with dexrazoxane, both in single arm and randomized cross-over studies, have generally shown no change in anthracycline metabolism, including pharmacokinetic parameters of alpha, beta, and gamma half-lives, area-under-the-curve, or clearance. There is no pharmacokinetic interaction of dexrazoxane on anthracycline metabolism and, therefore, pharmacokinetics cannot account for the cardioprotective effects described for dexrazoxane.