Genetic toxicology of remifentanil, an opiate analgesic.
Compounds that interact with opioid receptors are commonly used as analgesics. Opioid agonists vary in their potency and pharmacokinetic properties as well as in their affinity for distinct opioid receptors. The fentanyl opiate analogues are an important group of analgesics that interact with the mu opioid receptor. Remifentanil (GI87084) is a particularly interesting member of this group of opioids because its action is especially short in duration. This report examines the genetic toxicology of remifentanil. Remifentanil was not genotoxic in an Ames test, an in vitro chromosome aberration assay in Chinese hamster ovary cells, an in vivo micronucleus assay in rat erythrocytes, or an in vivo/in vitro unscheduled DNA synthesis assay in rat hepatocytes. In the in vitro L5178Y tk(+/-) mouse lymphoma assay, remifentanil produced a genotoxic response at dose levels >or=308 microg/mL only in the presence of rat liver S9 metabolic activation; primarily tiny and small mutant colonies were produced. This pattern of activity in a battery of genetic toxicology assays is not unique to remifentanil, but has also been observed for other pharmaceuticals, including the opioid fentanyl. A weight-of-evidence analysis, taking into consideration genotoxic mechanisms, in vivo results, and the conditions of clinical use, suggests remifentanil does not pose a genotoxic risk to patients.
Allen
Jane S
JS
GlaxoSmithKline, Research Triangle Park, North Carolina 27709, USA. lmw2024@gsk.com
Campbell
James A
JA
Cariello
Neal F
NF
Kutz
Stephen A
SA
Thilagar
Arul
A
Xu
Jing
J
Ham
Andrea L
AL
Mitchell
Ann D
AD
D000701:Analgesics, Opioid / Q000633:toxicity*; D000818:Animals; D016466:CHO Cells; D002869:Chromosome Aberrations / Q000139:chemically induced; D006224:Cricetinae; D004260:DNA Repair / Q000187:drug effects / Q000235:genetics; D004912:Erythrocytes / Q000187:drug effects; D005260:Female; D022781:Hepatocytes / Q000187:drug effects; D007940:Leukemia L5178 / Q000235:genetics / Q000378:metabolism; D008110:Liver Extracts / Q000378:metabolism; D008297:Male; D051379:Mice; D015162:Micronucleus Tests / Q000379:methods; D009152:Mutagenicity Tests / Q000379:methods; D010880:Piperidines / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D000077208:Remifentanil; D012486:Salmonella typhimurium / Q000187:drug effects / Q000235:genetics; D014407:Tumor Cells, Cultured
D000701:Analgesics, Opioid; D008110:Liver Extracts; D010880:Piperidines; D000077208:Remifentanil