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.
Its very bitter taste was usually disguised with herbs and spices; however, this did not prevent scurvygrass drinks and sandwiches from becoming a popular fad in the UK until the middle of the nineteenth century, when citrus fruits became more readily available.West Indian limes began to supplement lemons, when Spains alliance with France against Britain in the Napoleonic Wars made the supply of Mediterranean lemons problematic, and because they were more easily obtained from Britains Caribbean colonies and were believed to be more effective because they were more acidic. It was the acid, not the (then-unknown) Vitamin C that was believed to cure scurvy. In fact, the West Indian limes were significantly lower in Vitamin C than the previous lemons and further were not served fresh but rather as lime juice, which had been exposed to light and air, and piped through copper tubing, all of which significantly reduced the Vitamin C. Indeed, a 1918 animal experiment using representative samples of the Navy and Merchant Marines lime juice showed that it had virtually no antiscorbutic power at all.The belief that scurvy was fundamentally a nutritional deficiency, best treated by consumption of fresh food, particularly fresh citrus or fresh meat, was not universal in the 19th and early 20th centuries, and thus sailors and explorers continued to have scurvy into the 20th century. For example, the Belgian Antarctic Expedition of 1897–1899 became seriously affected by scurvy when its leader, Adrien de Gerlache, initially discouraged his men from eating penguin and seal meat.