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ToxSci Advance Access published online on October 31, 2006
Toxicological Sciences, doi:10.1093/toxsci/kfl148
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© The Author 2006. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Received July 20, 2006
Accepted October 12, 2006

Genetic Toxicology

Evidence that Oxymorphone-Induced Increases in Micronuclei Occur Secondary to Hyperthermia

Dana L. Shuey 1 *, Ramadevi Gudi 2, Ljubica Krsmanovic 2, and Ronald J. Gerson 1

1 Endo Pharmaceuticals Inc., 100 Endo Blvd., Chadds Ford, PA 19350
2 BioReliance, 9630 Medical Center Drive, Rockville, MD 20850

* To whom correspondence should be addressed.
Dana L. Shuey, E-mail: shuey.dana{at}endo.com


  Abstract

Oxymorphone is a potent opioid analgesic. Oral administration of oxymorphone to rats at doses ≥20 mg/kg, and mice at 500 mg/kg produced an increase in micronucleated polychromatic erythrocytes (MPCEs). Oxymorphone does not produce chromosome aberrations in vitro, suggesting that the increased MPCEs in vivo may involve indirect mechanisms. Opioids are known to affect thermoregulatory mechanisms. Changes in body temperature can increase the incidence of MPCEs in rodents. Studies were conducted to examine the relationship between increased MPCEs in rats given oxymorphone and changes in body temperature. Single oral doses of oxymorphone associated with increased MPCEs (20, 40 mg/kg) also produced a marked, rapid increase in body temperature. When animals were pretreated with sodium salicylate (SS), peak body temperature was lower, and returned to baseline more quickly than when oxymorphone was given alone. MPCEs were evaluated in rats after administration of oxmorphone (40 mg/kg) alone, or following pretreatment with an oral dose of SS. Oxymorphone alone produced a statistically significant increase in the incidence of MPCEs (3.6 per 1000 PCEs vs. 0.4 in controls). The number of MPCEs in animals pretreated with SS was similar to controls. SS alone had no effect on the number of MPCEs. Systemic oxymorphone exposure was not affected by SS pretreatment; maximum plasma concentration (Cmax) and area under the curve (AUC) values were similar after administration of oxymorphone alone or following pretreatment with SS. These results indicate that the increased incidence of MPCEs following oxymorphone administration is directly related to increased body temperature.

Keywords: Opioid; genotoxicity; thermoregulation; clastogenicity.
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