Inhibition of (mono)amine oxidase activity and prevention of ifosfamide encephalopathy by methylene blue

Abstract

The clinical application of ifosfamide is hampered by a central nervous side effect, the so-called ifosfamide encephalopathy. Methylene blue is effective in prophylaxis and reversal of this side effect. In the present study, the in vitro inhibition of (mono)amine oxidases by methylene blue is demonstrated in two different experimental systems. The results provide an explanation for the preventive action of methylene blue in ifosfamide neurotoxicity, because the generation of chloroacetaldehyde (a potential neurotoxin of ifosfamide metabolism) is prevented in liver mitochondria and extrahepatic tissues. Generation of alkylating metabolites was also studied in rat liver perfusions, and methylene blue did not show any inhibition of ifosfamide activation. From these data, we conclude that the clinical effectiveness of methylene blue in treatment and prevention of ifosfamide encephalopathy might be based on inhibition of (mono)amine oxidases. Hepatic bioactivation of ifosfamide is not influenced by methylene blue.