Busulfan is a small, highly lipophilic molecule that easily crosses the blood
brain barrier. Following absorption, 32% and 47% of busulfan are bound to plasma
proteins and red blood cells, respectively.
Busulfan absorption from the gastrointestinal tract is essentially complete.
This has been demonstrated in radioactive studies after both intravenous and
oral administration of 35S-busulfan, 14C-busulfan, and
3H-busulfan. Following intravenous administration of a single therapeutic
dose of 35S-busulfan, there was rapid disappearance of radioactivity
from the blood and 90% to 95% of the 35S-label disappeared within
3 to 5 minutes after injection. After either oral or intravenous administration
of 35S-busulfan, 45% to 60% of the radioactivity was recovered in
the urine in the 48 hours after administration; the majority of the total urinary
excretion occurring in the first 24 hours. Over 95% of the urinary 35S-label
occurs as 35S-methanesulfonic acid. Oral and intravenous administration
of 1,4-14C-busulfan showed the same rapid initial disappearance of
plasma radioactivity as observed following the administration of 35S-labeled
drug. Cumulative radioactivity in the urine after 48 hours was 25% to 30% of
the administered dose (contrasting with 45% to 60% for 35S-busulfan),
and suggests a slower excretion of the alkylating portion of the molecule and
its metabolites than for the sulfonoxymethyl moieties. Regardless of the route
of administration, 1,4-14C-busulfan yielded a complex mixture of
at least 12 radiolabeled metabolites in urine; the main metabolite being 3-hydroxytetrahydrothiophene-1,1-dioxide.
Pharmacokinetic studies employing 3H-busulfan labeled on the tetramethylene
chain confirmed a rapid initial clearance of the radioactivity from plasma,
irrespective of whether the drug was given orally or intravenously.
A study compared a 2-mg single IV bolus injection to a single oral dose of
a 2-mg tablet of nonradioactive busulfan in 8 adult patients 13 to 60 years
of age. The study demonstrated that the mean Â± SD absolute bioavailability was
80% Â± 20% in adults. However, the absolute bioavailability for 8 children 1.5
to 6 years of age was 68% Â± 31%.
In another study of 2, 4, and 6 mg of busulfan, given as a single oral dose
on consecutive days (starting with the lowest dose) in 5 adult patients, the
mean dose-normalized (to 2 mg dose) area under the plasma concentration-time
curve (AUC) was about 130 ng•hr/mL, while the mean intra- and inter-patient
variability was about 16% and 21%, respectively. Busulfan was eliminated with
a plasma terminal elimination half-life (t1/2) of about 2.6 hours, and demonstrated
linear kinetics within the range of 2 to 6 mg for both the maximum plasma concentration
(Cmax) and AUC. The mean Cmax for the 2-, 4-, and 6-mg doses (after dose normalization
to 2 mg) was about 30 ng/mL. A recent study of 4 to 8 mg as single oral doses
in 12 patients showed that the mean Â± SD Cmax (after dose normalization to 4
mg) was 68.2 Â± 24.4 ng/mL, occurring at about 0.9 hours and the mean Â± SD AUC
(after dose normalization to 4 mg) was 269 Â± 62 ng•hr/mL. These results
are consistent with previous results. In addition, the mean Â± SD elimination
half-life was 2.69 Â± 0.49 hours.
The elimination of busulfan appears to be independent of renal function. This
probably reflects the extensive metabolism of the drug in the liver, since less
than 2% of the administered dose is excreted in the urine unchanged within 24
hours. The drug is metabolized by enzymatic activity to at least 12 metabolites,
among which tetrahydrothiophene, tetrahydrothiophene 12-oxide, sulfolane, and
3-hydroxysulfolane were identified. These metabolites do not have cytotoxic
There is no experience with the use of dialysis in an attempt to modify the
clinical toxicity of busulfan. One technical difficulty would derive from the
extremely poor water solubility of busulfan. Additionally, all studies of the
metabolism of busulfan employing radiolabeled materials indicate rapid chemical
reactivity of the parent compound with prolonged retention of some of the metabolites
(particularly the metabolites arising from the "alkylating" portion
of the molecule). The effectiveness of dialysis at removing significant quantities
of unreacted drug would be expected to be minimal in such a situation.
Currently, there are no available data on the effect of food on busulfan bioavailability.
Pharmacokinetics in Hemodialysis Patients: The impact of hemodialysis
on the clearance of busulfan was determined in a patient with chronic renal
failure undergoing autologous stem cell transplantation. The apparent oral clearance
of busulfan during a 4-hour hemodialysis session was increased by 65%, but the
24-hour oral clearance of busulfan was increased by only 11%.
The incidence of veno-occlusive disease was higher (33.3% versus 3.0%) in patients
with busulfan AUC0-6hr >1,500 µM.min (Css >900
mcg/L) compared to patients with busulfan AUC0-6hr <1,500 µM.min
(Css <900 mcg/L) (see WARNINGS).
Drug Interactions: Itraconazole reduced busulfan clearance by up to
25% in patients receiving itraconazole compared to patients who did not receive
itraconazole. Higher busulfan exposure due to concomitant itraconazole could
lead to toxic plasma levels in some patients. Fluconazole had no effect on the
clearance of busulfan. Patients treated with concomitant cyclophosphamide and
busulfan with phenytoin pretreatment have increased cyclophosphamide and busulfan
clearance, which may lead to decreased concentrations of both cyclophosphamide
and busulfan. However, busulfan clearance may be reduced in the presence of
cyclophosphamide alone, presumably due to competition for glutathione.
Diazepam had no effect on the clearance of busulfan. No information is available
regarding the penetration of busulfan into brain or cerebrospinal fluid. Biochemical
Pharmacology: In aqueous media, busulfan undergoes a wide range of nucleophilic
substitution reactions. While this chemical reactivity is relatively non-specific,
alkylation of the DNA is felt to be an important biological mechanism for its
cytotoxic effect. Coliphage T7 exposed to busulfan was found to have the DNA
crosslinked by intrastrand crosslinkages, but no interstrand linkages were found.
The metabolic fate of busulfan has been studied in rats and humans using 14C-
and 35S-labeled materials. In humans, as in the rat, almost all of
the radioactivity in 35S-labeled busulfan is excreted in the urine
in the form of 35S-methanesulfonic acid. Roberts and Warwick demonstrated
that the formation of methanesulfonic acid in vivo in the rat is not
due to a simple hydrolysis of busulfan to 1,4-butanediol, since only about 4%
of 2,3-14C-busulfan was excreted as carbon dioxide, whereas 2,3-14C-1,4-butanediol
was converted almost exclusively to carbon dioxide. The predominant reaction
of busulfan in the rat is the alkylation of sulfhydryl groups (particularly
cysteine and cysteine-containing compounds) to produce a cyclic sulfonium compound
which is the precursor of the major urinary metabolite of the 4-carbon portion
of the molecule, 3-hydroxytetrahydrothiophene-1,1-dioxide. This has been termed
a "sulfur-stripping" action of busulfan and it may modify the function
of certain sulfur-containing amino acids, polypeptides, and proteins; whether
this action makes an important contribution to the cytotoxicity of busulfan
The biochemical basis for acquired resistance to busulfan is largely a matter
of speculation. Although altered transport of busulfan into the cell is one
possibility, increased intracellular inactivation of the drug before it reaches
the DNA is also possible. Experiments with other alkylating agents have shown
that resistance to this class of compounds may reflect an acquired ability of
the resistant cell to repair alkylation damage more effectively.
Clinical Studies: Although not curative, busulfan reduces the total
granulocyte mass, relieves symptoms of the disease, and improves the clinical
state of the patient. Approximately 90% of adults with previously untreated
chronic myelogenous leukemia will obtain hematologic remission with regression
or stabilization of organomegaly following the use of busulfan. It has been
shown to be superior to splenic irradiation with respect to survival times and
maintenance of hemoglobin levels, and to be equivalent to irradiation at controlling
It is not clear whether busulfan unequivocally prolongs the survival of responding
patients beyond the 31 months experienced by an untreated group of historical
controls. Median survival figures of 31 to 42 months have been reported for
several groups of patients treated with busulfan, but concurrent control groups
of comparable, untreated patients are not available. The median survival figures
reported from different studies will be influenced by the percentage of "poor
risk" patients initially entered into the particular study. Patients who
are alive 2 years following the diagnosis of chronic myelogenous leukemia, and
who have been treated during that period with busulfan, are estimated to have
a mean annual mortality rate during the second to fifth year which is approximately
two thirds that of patients who received either no treatment, conventional x-ray
or 32P-irradiation, or chemotherapy with minimally active drugs.
Busulfan is clearly less effective in patients with chronic myelogenous leukemia
who lack the Philadelphia (Ph1) chromosome. Also, the so-called "juvenile"
type of chronic myelogenous leukemia, typically occurring in young children
and associated with the absence of a Philadelphia chromosome, responds poorly
to busulfan. The drug is of no benefit in patients whose chronic myelogenous
leukemia has entered a "blastic" phase.
MYLERAN should not be used in patients whose chronic myelogenous leukemia has
demonstrated prior resistance to this drug.
MYLERAN is of no value in chronic lymphocytic leukemia, acute leukemia, or
in the "blastic crisis" of chronic myelogenous leukemia.