title: An evaluation of the genotoxicity of the antitussive drug Dextromethorphan.
abstract: Dextromethorphan (DMP) is an effective and widely used antitussive drug. While DMP has over a 50 year safe-marketing history, the only available genotoxicity data was an unpublished, negative Ames assay (Roche). Lack of a complete genotoxicity profile on DMP, specifically covering the chromosomal damage endpoint, prompted a regulatory request for an in vitro chromosome aberration assay. In accordance with EC and CPMP Guidance, we evaluated data for a number of chemicals with a structural relationship to DMP. DMP contains no structural alerts for genotoxicity or carcinogenicity using the Deductive Estimation of Risk from Existing Knowledge (DEREK) software tool, confirming the negative results obtained in the existing Ames assay. This is also consistent with the mostly negative genotoxicity and carcinogenicity data available on structurally related chemicals including morphine, codeine, nalbuphine, buprenorphine, naloxone, hydromorphone, levorphanol, and oxycodone. A state-of-the-science, in vitro chromosome aberration assay was also conducted, which demonstrated a lack of genotoxicity for DMP. The overall weight of evidence for DMP and its structural analogues, supports the conclusion that this class of phenanthrene-based chemicals, and DMP, in particular, are not genotoxic in vitro or in vivo, and do not represent a carcinogenic risk to patients.
authors.affiliation: The Procter & Gamble Co, Miami Valley Innovation Center, P.O. Box 538707, Cincinnati, OH 45253, USA. aardema.mj@pg.com
authors.forename: Marilyn J
authors.initials: MJ
authors.lastname: Aardema
authors.forename: Steven H
authors.initials: SH
authors.lastname: Robison
authors.forename: David
authors.initials: D
authors.lastname: Gatehouse
authors.forename: Gail
authors.initials: G
authors.lastname: Johnston
mesh_terms: D000701:Analgesics, Opioid / Q000633:toxicity; D000818:Animals; D000996:Antitussive Agents / Q000633:toxicity*; D016466:CHO Cells; D002869:Chromosome Aberrations / Q000187:drug effects; D006224:Cricetinae; D003412:Cricetulus; D016208:Databases, Factual; D003915:Dextromethorphan / Q000633:toxicity*; D020407:Internet; D009152:Mutagenicity Tests; D009153:Mutagens; D018570:Risk Assessment; D013329:Structure-Activity Relationship
chemical_list: D000701:Analgesics, Opioid; D000996:Antitussive Agents; D009153:Mutagens; D003915:Dextromethorphan