COMPARATIVE CARDIAC TOXICITY OF THE IV ADMINISTERED BENZIMIDAZOLE PYRIDAZINON DERIVATIVE PIMOBENDAN AND ITS ENANTIOMERS IN FEMALE BEAGLE DOGS

The new positive-inotropic and vasodilatating drug Pimobendan (racemat e), 5-dihydro-6-[2-(4-methoxyphenyl)1H-benzimidazole-5 -yl]-5-methyl-3 (2-H)-pyridazinone, and its enantiomers were investigated with regard to their cardiotoxicity in young adult female Chbb: Beagle dogs. The racemate and the (-)-isomer (eutomer) were intravenously injected once daily for 4 consecutive weeks at doses of 0.25, 0.75 and 2.25 mg/kg, and the (+)-isomer (distomer) at doses of 0.75, 2.25 and 6.75 mg/kg, r espectively. Clinical signs, hematological, clinico-chemical, ophthalm ologic and electrophysiological parameters were monitored. Plasma conc entration-time profiles of the parent compound and the major metabolit e UD-CG 212 were established on day 1 and in week 4 using an HPLC assa y. Partial areas under the curves from 0.08 h to 1 h (AUC(0.08-1 h)) a s well as the plasma concentration at time point 0.5 h (C-0.5 h) were used for statistical calculations. Necropsy and histopathologic examin ation were performed after completion of the treatment period. Reducti on of the blood pressure occurred already at low dosages of the racema te and the eutomer, but only in high dose distomer-treated animals. A tendency to tachycardia developed only in high dose females receiving the racemate. Consequently, with respect to the pharmacological effect s and the adverse events, the racemate is equivalent to the eutomer. P lasma concentrations of parent compound and metabolite were dose-linea r for racemate, eutomer and distomer within the dose range 0.25-2.25 m g/kg.d at both time points. There were no significant effects of form or repeated administration. A moderate increase of AUC(0.08-1 h) and C -0.5 h could be seen on day 23 for the distomer indicating a stereosel ective metabolism of the latter. Histologic changes of the valvular an d parietal endocardium being termed jet lesion were observed after adm inistration of the racemate (greater than or equal to 0.75 mg/kg.d) an d the eutomer (greater than or equal to 0.25 mg/kg.d) at distinctly lo wer doses than after the distomer (greater than or equal to 2.25 mg/kg .d). Furthermore, extent and severity of the morphologic lesions were found to be higher in dogs exposed to the racemate or the eutomer than in those receiving the distomer. The results gave evidence that the s o-called cardiotoxicity by Pimobendan in dogs resulted from the exagge rated pharmacodynamic effect but not from the chemical nature of the c ompound per se. They corroborate also the previously raised assumption that the exaggerated pharmacodynamic activity of cardiotonic compound s in the broadest sense accounts for their morphologic adverse effects in experimental animals.