Search

The subchronic toxicity and toxicokinetics of a combination of rabeprazole sodium and sodium bicarbonate were investigated in dogs by daily oral administration for 13 consecutive weeks with a 4-week recovery period. The dose groups consisted of control (vehicles), (5 + 200), (10 + 400), and (20 + 800) mg/kg of rabeprazole sodium + sodium bicarbonate, 20 mg/kg of rabeprazole sodium only, and 800 mg/kg of sodium bicarbonate only. Esophageal ulceration accompanied by inflammation was observed in only one animal in the male (20 + 800) mg/kg rabeprazole sodium + sodium bicarbonate group. However, the severity of the ulceration was moderate, and the site of occurrence was focally extensive; thus, it was assumed to be a treatment-related effect of rabeprazole sodium + sodium bicarbonate. In the toxicokinetics component of this study, systemic exposure to rabeprazole sodium (AUC last and C max at Day 91) was greater in males than females, suggesting sex differences. AUC last and C max at Day 91 were increased compared to those on Day 1 in a dose-dependent manner. A delayed T max and no drug accumulation were observed after repeated dosage. In conclusion, we suggest under the conditions of this study that the no-observed-adverse-effect level (NOAEL) of the combination of rabeprazole sodium + sodium bicarbonate in male and female dogs is (10 + 400) and (20 + 800) mg/kg, respectively., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Rabeprazole sodium is a widely used drug for gastrointestinal disorders. Several analytical methods for identifying rabeprazole sodium and its impurities have been reported. However, the genotoxicity of rabeprazole sodium and its impurities is still unclear. Thus, it is necessary to develop analytical methods that can identify the structures of its impurities and evaluate their genotoxicity. Here, we used high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry for identifying the impurities in rabeprazole sodium enteric-coated tablets. Impurities in the samples were matched with synthesized impurities based on the exact mass and secondary mass spectrometry characteristics and then subjected to in silico analysis using the Derek and Sarah software, as well as in vitro genotoxicity evaluations. Our method successfully identified the impurities as 2-[[4-(3-methoxy propane)-3-methyl-N-oxido-2-pyridyl] methyl sulfonyl]-1H-benzimidazole (impurity I), 2-[[4-(3-methoxy propane)-3-methyl-2-pyridyl]methyl sulfonyl]-benzimidazole (impurity II), 2-[[4-(3-methoxy propane)-3-methyl-2-pyridyl] methionyl]-1H-benzimidazole (impurity III), and 2-mercapto benzimidazole (impurity IV). In silico analysis predicted that impurity III demonstrated a structural alert; thus, this impurity was evaluated for in vitro genotoxicity using the Ames test and chromosomal aberration assay. Impurity III at concentrations of 7.5-30 μg/mL had an aberration rate of over 5% with or without S-9 mix. Furthermore, impurity III at concentrations of 40-1000 μg/plate significantly increased the number of mutagenic colonies with or without S-9 mix. These results indicated that impurity III should be regulated to the limit of 0.01%.