Pathophysiological Factors in Busulfan-Associated Seizures and Hypothermia

Overview

Busulfan (Bu), used in conditioning prior to hematopoietic stem cell transplantation, crosses the blood-brain barrier and is metabolized into neurotoxic compounds such as sulfolane. Approximately 10% of patients receiving high-dose Bu experience seizures, with metabolites like sulfolane implicated in neurotoxicity and hypothermia. This study investigated Bu and its metabolites’ kinetics, behavioral effects, and neurotoxicity markers in patients and mice to elucidate mechanisms underlying CNS toxicity.

Background

Busulfan is an alkylating agent metabolized primarily in the liver via glutathione conjugation, producing metabolites including tetrahydrothiophene (THT), THT 1-oxide, sulfolane, and 3-hydroxysulfolane. These metabolites undergo further oxidation and are excreted mainly in urine. Bu readily crosses the blood-brain barrier, and its metabolites, particularly sulfolane, have been associated with neurotoxic effects such as convulsions and hypothermia in animal studies. Despite prophylactic anticonvulsants, seizures occur in a subset of patients receiving Bu, but the underlying mechanisms remain unclear.

Data Highlights

Key Findings

• Busulfan is metabolized via glutathione conjugation producing neurotoxic metabolites including sulfolane.
• Busulfan and its metabolites cross the blood-brain barrier, contributing to CNS exposure.
• Sulfolane induces convulsions and hypothermia in animal models, correlating with clinical seizure incidence in patients.
• Approximately 10% of patients receiving high-dose busulfan experience seizures despite anticonvulsant prophylaxis.
• Mouse behavioral studies showed neurotoxic effects and temperature changes after administration of busulfan metabolites.
• Ex vivo electrophysiology revealed effects of busulfan and sulfolane on neuronal activity, supporting their role in CNS toxicity.

Clinical Implications

Clinicians should be aware of the neurotoxic potential of busulfan metabolites, particularly sulfolane, which may contribute to seizures and hypothermia in patients undergoing HSCT conditioning. Monitoring and possibly adjusting anticonvulsant prophylaxis may be warranted. Understanding the metabolic pathways and CNS penetration of busulfan can guide safer dosing and management strategies to mitigate neurotoxicity risks.

Conclusion

Busulfan’s metabolism produces neurotoxic compounds that cross the blood-brain barrier and contribute to seizures and hypothermia observed clinically. These findings enhance understanding of busulfan-associated CNS toxicity and may inform improved prophylactic and therapeutic approaches.

References

1. Alm et al. 2024 -- Pathophysiological Factors Contributing to Seizures and Hypothermia Associated with Busulfan Treatment