DOSE-INDEPENDENT PHARMACOKINETICS OF THE CARDIOPROTECTIVE AGENT DEXRAZOXANE IN DOGS

A randomized, four-way cross-over design was used to assess the dispos ition of the cardioprotective agent, dexrazoxane, in four male beagle dogs following single I.V. administration of 10, 25, 50, and 100 mg kg (-1) doses. Parent drug was quantified in plasma and urine with a vali dated high-pressure liquid chromatographic-electrochemical assay. A tw o-compartment open model adequately described the dexrazoxane plasma c oncentration versus time data. The terminal half-life ranged between 1 .1 and 1.3 h and the apparent steady-state distribution volume was 0.6 7 L kg(-1). The systemic clearance (CL) ranged from 10.3 to 11.5 mL mi n(-1) kg(-1), while estimates of renal clearance approximated the glom erular filtration rate (GFR similar to 3.2-4.9 mL min(-1) kg(-1)). Ove r the dose range evaluated, CL was dose independent (ANOVA, p = 0.33), while concentration at the end of infusion (C-end) and the area under the concentration versus time curve (AUG) were directly proportional to the dose (r>0.999). The blood cell to plasma partitioning ratio was similar to 0.517 and drug was essentially unbound to plasma proteins (f(u) similar to 0.95). Dexrazoxane appeared to be subject to low orga n extraction, since the hepatic and renal drug extraction ratios were on the order of 0.228+/-0.054 and 0.184+/-0.024, respectively. These r esults suggest a relatively small drug distribution space (approximate ly equal to total-body water) and low tissue and plasma protein bindin g. In light of the low plasma protein binding and extraction ratio exh ibited by dexrazoxane, metabolic capacity and renal function would app ear to be the predominant variables affecting the CL of this drug. The constancy of the half-life, CL, and V-ss with increasing dose indicat es dose-independent disposition for dexrazoxane. Thus a linear increas e in the systemic exposure can be predicted over this dose range.