Busulfán

Busulfan (Myleran, GlaxoSmithKline, Busulfex IV, Otsuka America Pharmaceutical, Inc.) is a chemotherapy drug in use since 1959. It is a cell cycle non-specific alkylating antineoplastic agent, in the class of alkyl sulfonates. Its chemical designation is 1,4-butanediol dimethanesulfonate.

Busulfan was approved by the US Food and Drug Administration (FDA) for treatment of chronic myeloid leukemia (CML) in 1999. Busulfan was the mainstay of the chemotherapeutic treatment of chronic myeloid leukemia (CML) until it was displaced by the new gold standard, imatinib, though it is still in use to a degree as a result of the drug's relative low cost.

Busulfan is used in pediatrics and adults in combination with cyclophosphamide or fludarabine/clofarabine as a conditioning agent prior to bone marrow transplantation, especially in chronic myelogenous leukemia (CML) and other leukemias, lymphomas, and myeloproliferative disorders. Busulfan can control tumor burden but cannot prevent transformation or correct cytogenic abnormalities.

The drug was recently used in a study to examine the role of platelet-transported serotonin in liver regeneration.^[1]

Myleran is supplied in white film coated tablets with 2 mg of busulfan per tablet. After 2002, a great interest has appeared for intravenous presentations of busulfan. Busulfex is supplied as an intravenous solution with 6 mg/ml busulfan. Busulfex has proved equally effective as oral busulfan, with presumedly less toxic side effects. Pharmacokinetic and dynamic studies support this use, that has prompted its usage in transplantation regimes, particularly in frail patients. Fludarabine + busulfan is a typical example of this use.

La toxicidad puede incluir fibrosis pulmonar intersticial ("pulmón de busulfán"), hiperpigmentación , convulsiones , enfermedad venooclusiva hepática (EVOH) o síndrome de obstrucción sinusoidal (SOS), ^{[ 2 ] [ 3 ]} emesis y síndrome de emaciación . El busulfán también induce impotencia en los hombres (mata las células germinales), trombocitopenia , una condición de recuento y actividad plaquetaria reducida , y a veces aplasia medular . ^{[ 4 ]} Las convulsiones y la EVOH son preocupaciones graves con la terapia con busulfán y a menudo se utiliza profilaxis para evitar estos efectos. La EVOH hepática es una toxicidad limitante de la dosis. Los síntomas de la EVOH incluyen aumento de peso, bilirrubina elevada, hepatomegalia dolorosa y edema . La razón por la que el busulfán causa EVOH es en su mayoría desconocida y puede ser mortal. ^{[ 3 ]} El ursodiol puede considerarse para la profilaxis de la enfermedad venooclusiva.

Con frecuencia, se administran antieméticos antes del busulfán para prevenir los vómitos (emesis).

La fenitoína puede utilizarse simultáneamente para prevenir las convulsiones. El levetiracetam ha demostrado eficacia como profilaxis contra las convulsiones inducidas por busulfán. Las benzodiazepinas también pueden utilizarse para las convulsiones inducidas por busulfán. ^{[ 5 ]}

El busulfán está catalogado por la IARC como un carcinógeno del Grupo 1 .

Como terapia adyuvante con ciclofosfamida para el acondicionamiento previo al trasplante de médula ósea en adultos y niños >12  kg, el busulfán intravenoso (IV) (Bulsulfex) se dosifica a 0,8  mg/kg cada seis horas durante 16 dosis (cuatro días). El busulfán IV se administra generalmente durante dos horas. Tanto las formulaciones IV como las orales requieren agentes antieméticos profilácticos administrados antes de la dosis de busulfán y antieméticos programados administrados posteriormente. La biodisponibilidad oral del busulfán muestra una gran variación interindividual. ^{[ 6 ]} Se recomienda tomar busulfán con el estómago vacío para reducir el riesgo de náuseas y vómitos .

Las concentraciones plasmáticas máximas se alcanzan una hora después de la administración oral. Aproximadamente el 30% del fármaco se une a proteínas plasmáticas, como la albúmina .

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 marrowablation 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).

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.

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.^[7] 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.^[8]

The molecular recognition of ureido-cyclodextrin with busulfan was investigated.^[9] 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.^[10]

• "Busulfan" . Portal de información sobre medicamentos . Biblioteca Nacional de Medicina de EE. UU. Archivado del original el 5 de julio de 2016.