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ToxSci Advance Access originally published online on October 31, 2006
Toxicological Sciences 2007 95(2):369-375; 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

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

Dana L. Shuey*,1, Ramadevi Gudi{dagger}, Ljubica Krsmanovic{dagger} and Ronald J. Gerson*

* Endo Pharmaceuticals Inc, 100 Endo Boulevard, Chadds Ford, Pennsylvania 19350 {dagger} BioReliance, 9630 Medical Center Drive, Rockville, Maryland 20850

1 To whom correspondence should be addressed. Fax: (484) 840-4291. E-mail: shuey.dana{at}endo.com.

Received July 20, 2006; accepted October 12, 2006


  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 and 40 mg/kg) also produced a marked, rapid increase in body temperature. When animals were pretreated with sodium salicylate, 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 oxymorphone (40 mg/kg) alone or following pretreatment with an oral dose of sodium salicylate. Oxymorphone alone produced a statistically significant increase in the incidence of MPCEs (3.6 per 1000 polychromatic erythrocytes vs. 0.4 in controls). The number of MPCEs in animals pretreated with sodium salicylate was similar to controls. Sodium salicylate alone had no effect on the number of MPCEs. Systemic oxymorphone exposure was not affected by sodium salicylate pretreatment; maximum plasma concentration (Cmax) and area-under-the-curve values were similar after administration of oxymorphone alone or following pretreatment with sodium salicylate. These results indicate that the increased incidence of MPCEs following oxymorphone administration is directly related to increased body temperature.

Key Words: opioid; genotoxicity; thermoregulation; clastogenicity.


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