title: Genotoxicity assessment of pirmenol, a new antiarrhythmic drug.
abstract: The genotoxicity of pirmenol was tested in the E. coli and S. typhimurium mutagenesis assay, an in vitro mammalian cell chromosome-aberration assay and an in vivo mouse micronucleus assay. The E. coli tester strain WP2s was exposed to concentrations of pirmenol as high as 10,000 micrograms/plate both in the absence (S9-) and presence (S9+) of metabolic activation. Five strains of S. typhimurium (TA98, TA100, TA1535, TA1537, TA1538) were exposed to concentrations of pirmenol as high as 5000 micrograms/plate in the absence and presence of S9. Pirmenol was not mutagenic toward either E. coli or S. typhimurium. Chinese hamster lung V79 cell cultures were exposed to pirmenol at concentrations of 500-2500 micrograms/ml (S9-) and 500-3000 micrograms/ml (S9+). Pirmenol increased the frequency of structural chromosome aberrations (SCAs). The minimum clastogenic concentration was 1500 micrograms/ml (both S9- and S9+) with a peak clastogenic response of 6% (S9-) and 34% (S9+) cells with aberrations. Although there were statistically significant results in the S9- experiment, the percent cells with aberration values for treated groups were within the historical control range (0-6%) of this laboratory. The observed effects in both the absence and presence of S9 appear at high concentrations compared to human circulating plasma levels of 1-3 micrograms/ml and the clastogenicity was confined to chromosome gaps and breaks. Consequently, this in vitro effect would not be expected to be reflected by either in vivo clastogenic or carcinogenic activity. This was supported by findings in the mouse micronucleus study of pirmenol in which single oral doses administered to male CD-1 mice at 5, 55, or 115 mg/kg (80% LD50) produced no statistically significant increases in the frequency of micronucleated polychromatic erythrocytes in bone marrow at 24, 48 or 72 h postdosing. Additionally, no evidence of carcinogenicity was seen in a mouse or rat bioassay.
authors.affiliation: Department of Pathology and Experimental Toxicology, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, MI 48105.
authors.forename: V
authors.initials: V
authors.lastname: Ciaravino
authors.forename: M L
authors.initials: ML
authors.lastname: Kropko
authors.forename: G
authors.initials: G
authors.lastname: Krishna
authors.forename: D K
authors.initials: DK
authors.lastname: Monteith
authors.forename: J C
authors.initials: JC
authors.lastname: Theiss
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology* / Q000633:toxicity; D001711:Biotransformation; D001853:Bone Marrow / Q000187:drug effects / Q000473:pathology; D002460:Cell Line; D002869:Chromosome Aberrations; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D004926:Escherichia coli / Q000187:drug effects; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D015162:Micronucleus Tests; D009152:Mutagenicity Tests; D009153:Mutagens / Q000494:pharmacology* / Q000633:toxicity; D010880:Piperidines / Q000494:pharmacology* / Q000633:toxicity; D012486:Salmonella typhimurium / Q000187:drug effects; D012854:Sister Chromatid Exchange / Q000187:drug effects*
chemical_list: D000889:Anti-Arrhythmia Agents; D009153:Mutagens; D010880:Piperidines; C024318:pirmenol