A review of the genotoxicity of marketed pharmaceuticals

Information in the 1999 Physician's Desk Reference as well as from the peer -reviewed published literature was used to evaluate the genotoxicity of mar keted pharmaceuticals. This survey is a compendium of genotoxicity informat ion and a means to gain perspective on the inherent genotoxicity of structu rally diverse pharmaceuticals. Data from 467 marketed drugs were collected. Excluded from analysis were anti-cancer drugs and nucleosides, which are e xpected to be genotoxic, steroids, biologicals and peptide-based drugs. Of the 467 drugs, 115 had no published gene-tox data. This group was comprised largely of acutely administered drugs such as antibiotics, antifungals, an tihistamines decongestants and anesthetics. The remaining 352 had at least one standard gene-tox assay result. Of these, 101 compounds (28.7%) had at least one positive assay result in the pre-ICH/OECD standard four-test batt ery (bacterial mutagenesis, in vitro cytogenetics, mouse lymphoma assay (ML A). in vivo cytogenetics). Per assay type, the percentage of positive compo unds was: bacterial mutagenesis test, 27/323 (8.3%); in vitro cytogenetics 55/222 (24.8%); MLA 24/96 (25%); in vivo cytogenetics 29/252 (11.5%). Of th e supplemental genetic toxicology test findings reported, the sister chroma tid exchange (SCE) assay had the largest percentage of positives 17/39 (43. 5%) and mammalian mutagenesis assays (excluding MLA) had the lowest percent age of positives 2/91 (2.2%). The predictive value of genetic toxicology fi ndings for 2-year bioassay outcomes is difficult to assess since carcinogen icity can occur via non-genotoxic mechanisms. Nevertheless, the following s urvey findings were made: 201 drugs had both gene-tox data and rodent carci nogenicity data. Of these, 124 were negative and 77 were equivocal or posit ive for carcinogenicity in at least 1 gender/1 species. Of the 134 non-carc inogens, 100 had no positive gene-tox findings. Of the remaining 24, 19 wer e positive in in vitro cytogenetics assays. Among the 77 compounds that exh ibited equivocal or positive effects in carcinogenesis studies, 26 were pos itive in gene-tox assays and 51 were negative. Of the 51 negatives, 47 had multiple negative gene-tox assay results suggesting that these are probably non-genotoxic carcinogens. Statistical analyses suggested that no combinat ion of gene-tox assays provided a higher predictivity of rodent carcinogene sis than the bacterial mutagenicity test itself. (C) 2001 Elsevier Science B.V. All rights reserved.