EXPERIMENTAL STUDIES ON THE TOXICITY OF DIPERDIPINE FOLLOWING ORAL AND PARENTERAL APPLICATION

Diperdipine (ethyl-(beta-piperidinoethyl)-2,6-dimethyl-4- itrophenyl)- 1,4-dihydropyridine-3,5-dicarboxylate, CAS 149543-07-7), a new calcium antagonist, will be used for the treatment of hypertension, angina pe ctoris and dysrhythmic conditions. The studies conducted were carried out to evaluate the risk following oral and intravenous application of diperdipine. In accordance with the administration route envisaged fo r man the drug was applied by oral and intravenous administration. Stu dies were performed on the acute and subchronic toxicity local toleran ce and mutagenic potential. The single application of diperdipine to m ice and rats by gavage caused intolerance reactions starting at the lo west tested dose level of 200 mg/kg b.w. p.o. (mice) and at 250 mg/kg b.w. po. (rats). After single intravenous injection intolerance reacti ons occurred starting at the lowest tested close level of 10 mg/kg b.w . for mice and rats. The test substance proved to be only mildly toxic after repeated (up to 3 months) oral administration. In the rat, toxi c effects occurred from 15 mg diperdine/kg b.w./day p.o. onwards. Targ et organ is the liver with a miliary/submiliary hepatocellular necrosi s. No mutagenic potential was observed. The therapeutic index (ratio o f the toxic dose in animals and the therapeutic human dose) for oral a dministration of diperdipine is at least 20, for i.v. administration a t least 40 depending on animal species, frequency of administration, d ose levels employed and the toxicological question posed.