Journal Article

Hemangiosarcoma in Mice Administered Pregabalin: Analysis of Genotoxicity, Tumor Incidence, and Tumor Genetics

David Pegg, Michael Bleavins, James Herman, Zbigniew Wojcinski, Michael Graziano, Judith Henck, Kay A. Criswell, Timothy Anderson and Steven Duddy

in Toxicological Sciences

Volume 128, issue 1, pages 9-21
Published in print July 2012 | ISSN: 1096-6080
Published online April 2012 | e-ISSN: 1096-0929 | DOI: http://dx.doi.org/10.1093/toxsci/kfs146
Hemangiosarcoma in Mice Administered Pregabalin: Analysis of Genotoxicity, Tumor Incidence, and Tumor Genetics

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Pregabalin, (S)-3-(aminomethyl)-5-methylhexanoic acid, binds with high affinity to the α2δ subunit of voltage-gated calcium channels and exerts analgesic, anxiolytic, and antiseizure activities. Two-year carcinogenicity studies were completed in B6C3F1 and CD-1 mice and two separate studies in Wistar rats. Doses in mice were 200, 1000, and 5000 mg/kg/day, with systemic exposures (AUC0–24 h) up to 31 times the mean exposure in humans, given the maximum recommended clinical dose. In rats, doses were 50, 150, and 450 mg/kg/day in males and 100, 300, and 900 mg/kg/day in females; systemic exposures up to 24 times were achieved in clinical trials. In both strains of mice, pregabalin treatment was associated with an increased incidence of hemangiosarcoma primarily in liver, spleen, and bone marrow. The incidence of hemangiosarcoma was higher in B6C3F1 mice than in CD-1 mice, consistent with its spontaneous incidence. Pregabalin did not increase the incidence of any other tumor type in rats and was not genotoxic, based on an extensive battery of in vivo and in vitro tests in bacterial and mammalian systems. Thus, pregabalin is a single-species, single tumor–type, nongenotoxic mouse carcinogen. Hemangiosarcomas occurring in mice treated with pregabalin were genotypically distinct from hemangiosarcomas induced by genotoxic carcinogens in humans with respect to ras and p53 mutation patterns and were similar to spontaneous tumors. Furthermore, there was a strong association between pregabalin treatment and bone marrow changes in these studies in mice, suggesting a possible link between the effects observed in bone marrow and the increase in tumor incidence in pregabalin-treated mice.

Keywords: nongenotoxic; rodent; carcinogenesis; hemangiosarcoma

Journal Article.  10522 words.  Illustrated.

Subjects: Medical Toxicology ; Toxicology (Non-medical)

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