About 30% of the drug is bound to plasma proteins, such as albumin. Busulfan therapeutic drug monitoring is completed based on trough (pre-dose) levels with a target six-hour area under the curve (AUC) of between 900 and 1500 micromolxmin. AUCs (six-hour) >1500 micromolxmin are associated with hepatic VOD and subsequent dose reduction should be considered. AUCs (six-hour) <900 micromolxmin are associated with incomplete bone marrow ablation and subsequent dose escalation should be considered. Dose adjustments are performed using first order kinetics, such that the adjusted dose = current dose × (target AUC/actual AUC). Drug interactions
Busulfan is metabolized via glutathione conjugation in the liver to inactive metabolites. Itraconazole can decrease busulfan clearance by up to 25%, resulting in AUC levels >1500 micromolxmin and increased risk of hepatic VOD. Concomitant use of acetaminophen within 72 hours of busulfan use can reduce busulfan clearance (resulting in increased busulfan AUC), as acetaminophen is also metabolized via glutathione and may deplete stores. Phenytoin increases hepatic clearance of busulfan (resulting in decreased busulfan AUC). However, clinical studies of busulfan were completed with patients taking phenytoin, so no empiric dose adjustment is necessary if patients are taking phenytoin with busulfan. Pharmacology
Busulfan is an alkylsulfonate. It is an alkylating agent that forms DNA-DNA interstrand crosslinks between the DNA bases guanine and adenine and between guanine and guanine. This occurs through an SN2 reaction in which the relatively nucleophilic guanine N7 attacks the carbon adjacent to the mesylate leaving group. DNA crosslinking prevents DNA replication.
Because the intrastrand DNA crosslinks cannot be repaired by cellular machinery, the cell undergoes apoptosis. Complexation
The molecular recognition of ureido-cyclodextrin with busulfan was investigated. The formation of complexes was observed with electrostatic interactions between urea and the sulfonate part of busulfan. Another structure was used for this complexation type, two disaccharidyl units connected by urea linkers to a diazacrown ether organizing platform. References
External links
"Busulfan". Drug Information Portal. U.S. National Library of Medicine.