A previous study revealed that
DQ-2511, a new gastroprokinetic
drug, induced
hemolytic anemia together with increased Heinz body formation, preceded by a marked decrease in erythrocyte
reduced glutathione (GSH) content, after 2 weeks of dosing onward in dogs. In this study, the effect of
DQ-2511 on erythrocytes in the early period of dosing, in comparison with that of
beta-acetylphenylhydrazine (APHZ), was investigated to confirm the difference between this
drug and APHZ in the mechanism of increased Heinz body formation.
DQ-2511 and APHZ were administered orally to beagle dogs for 1 week at dose levels of 600 and 4 mg/ kg, respectively. Dogs receiving APHZ showed
anemia after dosing for 7 days, together with an increase in
methemoglobin and Heinz body formation after 3 days of dosing. In contrast, blood GSH,
glutathione reductase, and
gamma-glutamylcysteine synthetase were only slightly decreased after dosing for 7 days. In dogs treated with
DQ-2511, erythrocyte GSH began to decrease after 1 day of treatment and was about 25% of the control value after 7 days; however, no changes were seen in blood
glutathione reductase, GSH
peroxidase, or
gamma-glutamylcysteine synthetase level. Hepatic GSH was decreased slightly. In another experiment, SD rats were administered
DQ-2511 and APHZ orally for 1 week at dose levels of 1600 and 15 mg/kg, respectively. Rats receiving
DQ-2511 showed no
anemia or any changes in erythrocyte GSH and Heinz body formation. In contrast, rats treated with APHZ showed a marked
anemia and increases in Heinz body formation and erythrocyte GSH. These results demonstrate that
DQ-2511 causes a marked decrease in GSH in dogs, resulting in Heinz body
anemia, whereas APHZ induces Heinz body formation after a significant increase in
methemoglobin, and suggest that impairment of the GSH redox cycle and
synthetases of GSH are not involved in the decreased GSH after
DQ-2511 treatment. This difference in effects on GSH content may indicate the existence of a species difference in the
anemia induced by
DQ-2511.