Genotoxicity from metronidazole detected in vitro, but not in vivo, in healthy dogs in a randomized clinical trial

Abstract

Abstract OBJECTIVE To determine whether metronidazole (MTZ), at recommended therapeutic dosages in dogs, induces peripheral blood cell (PMBC) genotoxicity, using the γ-H2AX assay as a sensitive measure of DNA breaks. The secondary aim was to assess dose-dependent genotoxicity in vitro in dog and cat PBMCs exposed to increasing MTZ concentrations. ANIMALS 12 healthy employee- and student-owned dogs and blood samples from 2 other healthy untreated dogs and 2 healthy untreated cats. PROCEDURES Screened dogs were randomized to receive lower-dose MTZ (7.5 mg/kg, PO, q 12 h) or higher-dose MTZ (20 mg/kg, PO, q 12 h) for 7 days. Blood was drawn at baseline, after the 1 week of treatment, and after a 1-week washout, for DNA damage assessment and serum MTZ concentration measurements. For in vitro studies, PBMCs from untreated healthy dogs and cats were exposed to 0 to 500 μg/mL MTZ. RESULTS No dogs showed a significant increase in DNA damage at these MTZ dosages for 1 week. The highest serum MTZ concentration observed 1 hour after dosing was 36 μg/mL. In vitro, MTZ led to a significant increase in DNA damage at 100 μg/mL in both canine and feline PBMCs. CLINICAL RELEVANCE Although MTZ was not significantly genotoxic in vivo in the healthy dogs in this study, MTZ was significantly genotoxic to canine PBMCs in vitro at 3-fold higher concentrations than those documented in vivo. The safety of MTZ in clinically ill dogs, which may have impaired MTZ clearance or DNA repair, should be assessed next.