Busulfan: Difference between revisions

{{Short description|Chemical compound}}

{{refimprove|date=April 2017}}

{{redirect-distinguish|Mitosan|Mitosene}}

| Watchedfields = changed

| verifiedrevid =

| width = 200px

| =

| tradename = Myleran

| =

| pregnancy_AU =

| =

| routes_of_administration = Oral,

| ATC_prefix = L01

| ATC_suffix = AB01

| legal_AU = S4

| legal_CA = Rx-only

| legal_UK = POM

| legal_US = Rx-only

| legal_EU = Rx-only

| legal_EU_comment =

| bioavailability = % (oral)

| metabolism = [[Liver]]

| excretion =

| = {{cascite|correct|}}

| IUPHAR_ligand = 7136

| IUPAC_name = -1,4-diyl dimethanesulfonate

| C=6 | H=14 | O=6 | S=2

| smiles = (=O)(OCCCCOS(=O)(=O)C

Busulfan 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 the mainstay of the [[chemotherapy|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.

in [[bone marrow transplantation]], especially in [[chronic myelogenous leukemia]] (CML) . 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.<ref>{{cite journal |=Lesurtel M, Graf R, Aleil B, Walther D, Tian Y, Jochum W, Gachet C, Bader M, Clavien P | title = Platelet-derived serotonin mediates liver regeneration | journal = Science | volume = 312 | issue = 5770 | pages = 104–7 | year = 2006 | pmid = 16601191 | doi = 10.1126/science.1123842}}</ref>

== Availability ==

Myleran is supplied in white film coated tablets with 2&nbsp;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&nbsp;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.

Toxicity may include interstitial [[pulmonary fibrosis]] ("busulfan lung"), [[hyperpigmentation]], [[seizures]], hepatic ([[veno-occlusive disease]]) (VOD) or sinusoidal obstruction syndrome (SOS),<ref name="pmid8932850">{{cite journal |vauthors=Grigg A, Gibson R, Bardy P, Szer J |title=Acute portal vein thrombosis after autologous stem cell transplantation |journal=Bone Marrow Transplant. |volume=18 |issue=5 |pages=949–53 |year=1996 |pmid=8932850 }}</ref><ref name="pmid15571949">{{cite journal |vauthors=Brisse H, Orbach D, Lassau N, Servois V, Doz F, Debray D, Helfre S, Hartmann O, Neuenschwander S |title=Portal vein thrombosis during antineoplastic chemotherapy in children: report of five cases and review of the literature |journal=Eur. J. Cancer |volume=40 |issue=18 |pages=2659–66 |year=2004 |pmid=15571949 |doi=10.1016/j.ejca.2004.06.013 }}</ref> emesis, and [[wasting syndrome]]. Busulfan also induces impotence in males (kills germ cells), [[thrombocytopenia]], a condition of lowered blood [[platelet]] count and activity, and sometimes medullary [[aplasia]].<ref name="pmid13489262">{{cite journal |vauthors=Hayhoe FG, Kok D |title=Medullary aplasia in chronic myeloid leukaemia during busulphan therapy |journal=Br Med J |volume=2 |issue=5059 |pages=1468–71 |year=1957 |pmid=13489262 |pmc=1962898 |doi= 10.1136/bmj.2.5059.1468}}</ref> Seizures and VOD are serious concerns with busulfan therapy and prophylaxis is often utilized to avoid these effects. Hepatic VOD is a dose-limiting toxicity. Symptoms of VOD include weight gain, elevated [[bilirubin]], painful [[hepatomegaly]], and [[edema]]. The reason busulfan causes VOD is mostly unknown and can be deadly. <ref name="pmid15571949" /> [[Ursodiol]] may be considered for prophylaxis of veno-occlusive disease.

Antiemetics are often administered prior to busulfan to prevent vomiting (emesis).

[[Phenytoin]] may be used concurrently to prevent the seizures. [[Levetiracetam]], has shown efficacy for the prophylaxis against busulfan-induced seizures. Benzodiazepines can also be used for busulfan-induced seizures.<ref name="Eberly-2008">{{ journal | = Eberly AL Anderson GD Bubalo JS McCune JS | title = Optimal prevention of seizures induced by high-dose busulfan | journal = Pharmacotherapy | volume = 28 | issue = 12 | pages = | = | = | doi = 10.1592/phco.28.12.1502 | = }}</ref>

==Dosing, administration, and pharmacokinetics==

As an adjunct therapy with [[cyclophosphamide]] for conditioning prior to [[bone marrow transplantation]] in adults and children >12&nbsp;kg, intravenous (IV) busulfan (Bulsulfex) is dosed at 0.8&nbsp;mg/kg every six hours for 16 doses (four days). IV busulfan is usually administered over two hours. Both IV and oral formulations require prophylactic [[antiemetic]] agents administered prior to the busulfan dose and scheduled [[antiemetics]] administered thereafter. Oral bioavailability of busulfan shows a large interindividual variation.<ref name="pmid7919328">{{cite journal |vauthors=Hassan M, Ljungman P, Bolme P, Ringdén O, Syrůcková Z, Békàssy A, Starý J, Wallin I, Kållberg N |title=Busulfan bioavailability |journal=Blood |volume=84 |issue=7 |pages=2144–50 |year=1994 |pmid=7919328 |doi= 10.1182/blood.V84.7.2144.2144|url=http://www.bloodjournal.org/cgi/pmidlookup?view=long&pmid=7919328 |access-date=2018-02-04|doi-access=free }}</ref> Taking busulfan on an empty stomach is recommended to reduce the risk of [[nausea]] and [[emesis]].

Peak plasma concentrations are achieved within one hour of oral administration. 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==

[[]] [[guanine]][[adenine]] .<ref>{{cite journal |=Iwamoto T, Hiraku Y, Oikawa S, Mizutani H, Kojima M, Kawanishi S |title=DNA intrastrand cross-link at the 5'-GA-3' sequence formed by busulfan and its role in the cytotoxic effect |journal=Cancer Sci. |volume=95 |issue=5 |pages=454–8 |=2004 |pmid=15132775 |doi=10.1111/j.1349-7006.2004.tb03231.x}}</ref> This occurs through an [[SN2]] reaction in which the relatively [[nucleophilic]] guanine N7 attacks the carbon adjacent to the [[mesylate]] leaving group. cannot be repaired by cellular machinery the cell undergoes [[apoptosis]].<ref>{{cite journal |=Karstens A, Kramer I |title=Chemical and physical stability of diluted busulfan infusion solutions |journal=EJHP Science |volume=13 |pages=40–7 |year=2007 }}</ref>

The molecular recognition of ureido-[[cyclodextrin]] with busulfan was investigated.<ref>{{cite journal |=Menuel S, Joly JP, Courcot B, Elysee J, Ghermani NE, Marsura A | title = Synthesis and inclusion ability of a bis-beta-cyclodextrin pseudo-cryptand towards Busulfan anticancer agent | journal = Tetrahedron | volume = 63 | issue = 7 | pages = 1706–14 | year = 2007 | doi = 10.1016/j.tet.2006.10.070}}</ref> The formation of complexes was observed with electrostatic interactions between urea and the [[sulfonate]] part of busulfan.

structure was used for this type, two disaccharidyl units connected by urea linkers to a diazacrown ether organizing platform.<ref>{{cite journal |=Porwanski S, Florence , Menuel S, Joly JP, Bulach V, Marsura A | title = Bis-beta-cyclodextrinyl- and bis-cellobiosyl-diazacrowns: synthesis and molecular complexation behaviors toward Busulfan anticancer agent and two basic aminoacids| journal = Tetrahedron | volume = 65 | issue = 31 | pages = 6196–6203| year = 2009 | doi = 10.1016/j.tet.2009.05.057}}</ref>

* {{cite web | url = https://druginfo.nlm.nih.gov/drugportal/name/busulfan | publisher = U.S. National Library of Medicine | work = Drug Information Portal | title = Busulfan }}

{{Portal bar | Medicine}}

[[Category:Alkylsulfonates]]

[[Category:Alkylating antineoplastic agents]]

[[Category:IARC Group 1 carcinogens]]

[[Category: ]]

[[Category: ]]

[[Category: ]]