ABSTRACT
The tolerance of the new calcium antagonist VULM 993 was investigated in a series of toxicological studies. The following results were obtained: the maximum tolerated oral dose in acute toxicity was 10,000 mg/kg for mice and 6600 mg/kg for rats, for venous administration it was 26.1 mg/kg in mice and 32.2 mg/kg in rats. In subacute oral toxicity test in rats, VULM 993 showed no toxic effect up to 300 mg/kg/d. The drug was not teratogenic in rats (5, 50 or 250 mg/kg/d, p.o.). VULM 993 did not show any positive response in tests for genotoxicity in vitro. Transplacental study of VULM 993 in rabbits indicated active placental barrier function in the late stage of pregnancy. The toxicological profile of VULM 993 is characterised by a high tolerance in all relevant species of experimental animals, and no biologically significant mutagenic potential was recorded.
Subject(s)
Calcium Channel Blockers/toxicity , Maternal-Fetal Exchange , Pyridines/therapeutic use , Spiro Compounds/therapeutic use , Administration, Oral , Animals , Biotransformation , Calcium Channel Blockers/administration & dosage , Calcium Channel Blockers/pharmacokinetics , Cell Line , Female , Injections, Intravenous , Male , Mice , Microsomes, Liver/metabolism , Mutagenicity Tests , Placenta/physiology , Pregnancy , Pyridines/administration & dosage , Pyridines/pharmacokinetics , Rabbits , Rats , Rats, Wistar , Salmonella typhimurium/drug effects , Spiro Compounds/administration & dosage , Spiro Compounds/pharmacokinetics , TeratogensABSTRACT
The induction of mutations at the HPRT locus and cytotoxicities of 4 vermiculin derivatives 2-4 and 6 were examined in V79 Chinese hamster cells and compared with those of the parent compound vermiculin (1). Derivatives prepared by hydrogenation were less toxic and mutagenic or non toxic and non mutagenic. The substitution at position 13 affected the evaluated biological effects. The results suggest that in vitro metabolism of vermiculin resulted in decreased cytotoxicity and mutagenicity.
