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PubMed2004

The impact of low-dose busulfan on clonal dynamics in nonhuman primates.

An understanding of the number and contribution of individual pluripotent hematopoietic stem cells (HSCs) to the formation of blood lineages has important clinical implications for gene therapy and stem cell transplantation. We have been able to efficiently mark rhesus macaque long-term repopulating stem and progenitor cells with retroviral vectors, and track their in vivo contributions to hematopoiesis using the linear amplification mediated-polymerase chain reaction (LAM-PCR) technique of insertion site analysis. We assessed the impact of busulfan on contributions of individual retrovirally marked clones to hematopoiesis. There were 2 macaques that received transplants of retrovirally transduced CD34(+) cells 2 years previously that were then treated with 4 mg/kg busulfan. Despite only transient and mild suppression of peripheral blood counts, the numbers of individual stem/progenitor clones contributing to granulocyte production decreased dramatically, by 80% in the first monkey and by 60% in the second monkey. A similar impact was seen on clones contributing to T cells. The clone numbers recovered gradually back toward baseline by 5 months following busulfan in the first monkey and by 3 months in the second monkey, and have remained stable for more than one year in both animals. Tracking of individual clones with insertion-site-specific primers suggested that clones contributing to hematopoiesis prior to busulfan accounted for the majority of this recovery, but that some previously undetected clones began to contribute during this recovery phase. These results indicate that even low-dose busulfan significantly affects stem and progenitor cell dynamics. The clonal diversity of hematopoiesis was significantly decreased after even a single, clinically well-tolerated dose of busulfan, with slow but almost complete recovery over the next several months, suggesting that true long-term repopulating stem cells were not permanently deleted. However, the prolonged period of suppression of many clones suggests that transplanted HSCs may have a marked competitive advantage if they can engraft and proliferate during this time period, and supports the use of this agent in nonmyeloablative regimens

Animals↗
PubMed2006

Pretransplant conditioning in adults and children: dose assurance with intravenous busulfan.

PURPOSE/OBJECTIVES: To provide clinical insights into dosing and administration of IV busulfan, a conditioning agent for hematopoietic stem cell transplantation (HSCT). DATA SOURCES: Review of published literature related to busulfan pretransplant conditioning using MEDLINE. Meeting abstracts, investigational protocols, and pharmaceutical manufacturers' package inserts also were reviewed. DATA SYNTHESIS: Busulfan is an effective myeloablative conditioning agent for HSCT. The IV formulation increases dose assurance and the ability to target a therapeutic window. Therapeutic drug monitoring ensures that targeted blood levels are achieved, especially in children, thereby preventing underdosing, which can lead to disease progression or rejection, as well as overdosing, which can cause an increased risk of toxic side effects. CONCLUSIONS: IV busulfan is a convenient, safe, and effective conditioning agent used in HSCT that has a predictable pharmacokinetic profile. IMPLICATIONS FOR NURSING: An understanding of the pharmacokinetic principles underlying the relationship between the therapeutic window for busulfan and optimal HSCT outcomes will facilitate proper dosing and administration of IV busulfan.

Administration, Oral↗
PubMed1986

Lack of ovarian responsiveness to gonadotropic hormones in infantile rats sterilized with busulfan.

Ovarian responsiveness to FSH and LH was examined in infantile rats treated in utero with busulfan (1,4-butanediol dimethanesulfate), a cytotoxic drug which has been shown to cause selective attrition of germ cells in the rat fetus. Pregnant Sprague-Dawley rats were injected ip on day 13 of gestation with busulfan (10 mg/kg BW) suspended in sesame oil or with sesame oil alone (control). Pups were killed on days 6, 8, 10, 12, or 14 postnatally, and trunk blood was collected. The ovaries were removed and either fixed for light microscopy or assessed for responsiveness to FSH and LH by their ability to produce net accumulations of cAMP and gonadal steroids in short term incubations. Ovaries, in which the germ cells were successfully destroyed, consisted of anastomotic cords of the intraovarian rete system surrounded by undifferentiated stromal tissue. A variable number of oocytes usually survived the busulfan treatment and were situated within the cords in irregularly defined follicles. Few treated oocytes proceeded to organize antral follicles by 14 days postnatally, but these follicles showed signs of normal theca and interstitial cell investment. A challenge of FSH or LH in vitro failed to stimulate net accumulations of cAMP, progesterone, androstenedione, or estradiol from treated ovaries whereas these responses were significantly stimulated in controls. Detectable levels of cAMP and steroids were, however, present in incubations of busulfan-treated ovaries on days 12 and 14, and these are likely attributable to the activity of antral follicles that survived the effects of busulfan. From day 8 to 12 plasma gonadotropin levels in treated animals rose significantly above those of controls suggesting that normal ovarian steroidogenesis is also suppressed in treated animals in vivo. Although direct effects of busulfan on somatic cells cannot be dismissed, these results suggest that the presence of germ cells is a prerequisite for the normal development of steroidogenic function in the rat ovary.

1-Methyl-3-isobutylxanthine↗
PubMed2005

Reduction of primordial follicles caused by maternal treatment with busulfan promotes endometrial adenocarcinoma development in donryu rats.

Ovarian dysfunction leading to hormonal imbalance plays a crucial role in uterine carcinogenesis in rats as well as women. However, the effects of a reduction in primordial follicles at birth on uterine adenocarcinoma development have hitherto not been determined. The present study was therefore conducted using female Donryu rats, a high incidence rat strain of uterine adenocarcinoma. The animals were maternally exposed to 2.5 or 5.0 mg/kg of busulfan on gestation day 14 to reduce primordial follicles, and were then initiated by intrauterine treatment with N-ethyl-N'-nitro-N-nitrosoguanidine at 11 weeks of age. Both busulfan treatment doses caused earlier occurrence of persistent estrus, with dose-dependence as compared to controls. At 15 months of age, the rats were euthanized. The incidence of uterine adenocarcinomas and multiplicity of uterine neoplastic lesions were significantly increased by the 5.0 mg/kg, but not the 2.5 mg/kg busulfan treatment. Morphologically, the ovaries exposed to busulfan treatment exhibited severe atrophy, with few or no follicles and corpus lutea. Serum 17beta-estradiol (E2), progesterone, and inhibin levels were significantly decreased in the busulfan treatment groups, with a clear dose-relation. Interestingly, only the 5.0 mg/kg busulfan treatment elevated the E2/progesterone ratio. These results provide evidence that the reduction of primordial follicles promotes uterine adenocarcinoma development in rats in association with an earlier occurrence of the persistent estrus status.

Adenocarcinoma↗
PubMed1988

Effects of busulfan on ovarian folliculogenesis, steroidogenesis and anti-müllerian activity of rat neonates.

Pregnant rats were injected with busulfan on day 12 or 18 of gestation and the ovaries of 5- and 10-day-old neonates were compared with control ones in terms of 1) folliculogenesis, 2) production of estradiol-17 beta and estrone in vitro, 3) aromatase and 3 beta-hydroxysteroid dehydrogenase/isomerase (3 beta-HSD) activities, and 4) anti-müllerian hormone. Injection of busulfan on day 12 led to a reduction in the number of germ cells and follicles, delayed the maturation of antral follicles and lowered estrogen production and aromatase and 3 beta-HSD activities. Anti-müllerian activity, present in ovaries from 10-day-old controls, was also depressed in busulfan-treated rats. No obvious effects were observed when busulfan was injected on day 18. Estrogen biosynthesis could be stimulated by gonadotropins at day 10 post-partum, indicating the presence of functional receptors to LH and/or FSH. These relationships are interpreted as indicating that ovarian cells retain their capacity to respond to hormonal challenge despite the morphological impairment induced by busulfan. Other factors which possibly interfere with ovarian activity in busulfan-treated rats are discussed.

3-Hydroxysteroid Dehydrogenases↗
PubMed1996

Aspects concerning busulfan pharmacokinetics and bioavailability.

Busulfan as a high-dose therapy is an important component of many of the myeloablative regimens for both allogeneic and autologous bone marrow transplantation (BMT) in adults and children. During the last decade, several studies have shown a wide inter- and intra-patient variability of busulfan disposition in adults and children. Some of the factors affecting the interpatient-variability were identified as circadian rhythmicity, age, disease, drug interaction, alteration in hepatic function and recently busulfan bioavailability. In adults, pharmacodynamic studies have shown a positive correlation between high-systemic exposure of the drug and venocclusive disease (VOD). However, pharmacodynamic studies in children did not establish any correlation between the systemic exposure and VOD. Drug-monitoring and dose adjustment in adults were used successfully to decrease the occurrence of VOD and mortality. It was observed that about 20% of the busulfan dose crosses the blood brain barrier. The high amount of the drug which enters the brain can probably be involved in the CNS toxicities reported. In children, a low rate of toxicity combined with a high rate of engraftment failure were observed. Several investigators have expressed their concern about the dosage in children and many suggested higher doses based on the body surface area for young children. However, recently it was shown that busulfan bioavailability varied by 2-fold in adults (0.5-1.03) while in children a 6-fold variation was observed (0.22-1.20). The access to an intravenous form of busulfan and a deeper understanding of pharmacodynamics of the drug might be essential to optimize the treatment, reach a successful engraftment and lower the therapy related toxicities.

Adolescent↗
PubMed1999

Proliferation of exogenously injected primordial germ cells (PGCs) into busulfan-treated chicken embryos.

AIM: This study was designed to investigate the effect of busulfan treatment on the proliferation of chicken primordial germ cells (PGCs) in vivo, focusing on the preferential settlement of PGCs onto the germinal ridges of chicken embryos. METHODS: Busulfan (250 ng/egg) was injected into the egg white of freshly oviposited fertilized eggs, which were then incubated. Embryonic development and viability were examined, and exogenous PGCs collected from embryonic blood vessels were injected into the germinal crescent region of recipient embryos. The number of PGCs resided onto germinal ridges of the right and left sides were compared. RESULTS: Busulfan had a slight harmful effect on the embryo viability and the PGCs proliferation. The number of PGCs resided onto the left side of germinal ridges was slightly higher as compared with the right side. CONCLUSION: Busulfan suppressed the viability of embryos and the proliferation of endogenous PGCs in the recipient embryos. However, the number of exogenous PGCs proliferated was higher in embryos treated with busulfan than those without busulfan. Data also suggest the possibility of a preferential residence of PGCs toward the left side of the germinal crescent region as compared with the right, which may be due to a more advanced functional development of the left gonad than the right.

Animals↗
PubMed2005

Overexpression of glutathione-S-transferase, MGSTII, confers resistance to busulfan and melphalan.

A major obstacle to hematopoietic gene therapy is the lack of appropriate in vivo selection protocols that can raise the presently low numbers of gene-altered stem cells to therapeutically useful levels. Overexpression of glutathione-S-transferases (GST), in combination with busulfan treatment, may provide an exploitable selection mechanism for hematopoietic gene therapy strategies. GST provides a major route of detoxification of a variety of xenobiotics, including alkylating agents used for myeloablative chemotherapy. The only known route of clearance of busulfan is by GST-mediated conjugation. Using a fibroblast cell line as a model, we have tested the effects of overexpression of three human GST (GSTA1, GSTP1, and MGSTII) on cell survival under a busulfan or melphalan challenge. In two separate assay formats using chronic exposure to busulfan, MGSTII conferred a reproducible twofold selective advantage. GSTA1 and GSTP1 had no effect on busulfan resistance, and melphalan resistance was not affected by expression of any of the GSTs in these assays. In an acute (24-hour) melphalan exposure assay, MGSTII conferred about a twofold selective advantage. Busulfan was not toxic in this assay. RTPCR analysis of human bone marrow CD34+ cells showed that MGSTII is not highly expressed in this stem/early progenitor population. These data indicate that MGSTII may be a useful selective agent in hematopoietic gene therapy.

Antigens, CD34↗
PubMed1989

Comparison of the mechanism of action of busulfan with hepsulfam, a new antileukemic agent, in the L1210 cell line.

1,7-Heptanediol disulfamate (hepsulfam, NSC 329680) is a new antileukemic agent with close structural similarity to busulfan. The mechanism of action of hepsulfam is not known and it has recently been entered into Phase I clinical trials by the National Cancer Institute. Waud et al. have recently shown that hepsulfam has good antitumor activity against mouse L1210 leukemia in vivo (Waud et al., Proc. Am. Assoc. Cancer Res., 29:333, 1988). In contrast, busulfan was inactive against this model tumor system. In the present study, we have compared the in vitro cytotoxicity of hepsulfam with that of busulfan and we also examined the ability of these compounds to induce DNA damage in the L1210 leukemia cell line. Our results show that L1210 leukemia cells were 7-fold more sensitive to hepsulfam than busulfan. Only hepsulfam produced an appreciable quantity of DNA interstrand cross-linking in L1210 cells, with the peak of cross-link formation being delayed 12 h following a 2-h drug treatment. In contrast, both compounds also produced DNA-protein cross-linking, again with the formation of peak levels being delayed 6-12 h after drug treatment. At equimolar concentrations, hepsulfam produced a greater quantity of DNA interstrand cross-links and DNA-protein cross-links than busulfan. In contrast, busulfan produced a greater quantity of DNA-protein cross-links, when compared to hepsulfam at equitoxic concentrations.

Animals↗
PubMed1980

beta 2-Adrenergic stimulation of erythropoiesis in busulfan treated mice.

The capability of chronic beta 2-adrenoceptor activation to effectively stimulate erythrocyte production in vivo was investigated in mice which had been treated with the hematopoiesis inhibiting agent busulfan. A relatively low dose (5 mg/kg i.p.) of busulfan produced moderate depression of erythropoiesis 10 days after a single injection, as determined by 59Fe-incorporation into erythrocytes. Administration of albuterol (1 mg/kg s.c. twice daily), a selective beta 2-adrenergic agonist, significantly enhanced erythropoiesis for 5--10 days after the injection of busulfan. In a long-term study with albuterol at the same dose a significant increase in hematocrit values as well as in the circulating erythrocyte mass was found in busulfan (5 mg/kg i.p. weekly) treated mice when compared to saline-busulfan treated control mice. Simultaneous injections of the beta-adrenergic blocking agent propanolol (4 mg/kg i.p.) diminished the effect of albuterol on erythropoiesis. Albuterol at a lower dose (0.1 mg/kg) had no significant effect on erythrocyte mass. In view of recent findings, which have shown that the proliferation of the pluripotent hemopoietic stem cell pool is blocked by busulfan, it is concluded that the main site of beta 2-adrenergic action on erythropoiesis is on the erythroid committed stem cell pool. In addition, enhanced release of erythropoietin from the kidney following the application of albuterol may contribute to beta 2-adrenergic stimulation of erythropoiesis.

Albuterol↗
PubMed1995

Use of a water-soluble busulfan formulation--pharmacokinetic studies in a canine model.

In a canine model we investigated the toxicity and pharmacokinetics of a water soluble busulfan preparation. Busulfan was dissolved in dimethylsulfoxide (DMSO) and administered either orally or intravenously in a single dose of 1 mg/kg. The application in either preparation was well tolerated. In seven dogs, peak levels in the range of 730 ng/mL to 1,000 ng/mL were measured after intravenous injection with an area under curve (AUC) of 75 ng.h/kg.mL to 146 ng.h/kg.mL. It was of note that even the oral administration of the same busulfan preparation resulted in AUC values in the same range as observed after parenteral application. The absorption rate of busulfan tablets in our model was as unpredictable as documented in clinical trials. On the basis of the present study, clinical trials using busulfan dissolved in DMSO given either intravenously or orally appear warranted. This approach should lead to predictable blood levels, reduced toxicity, and increased efficacy of busulfan-containing regimens.

Administration, Oral↗
PubMed1993

Randomized comparison of busulfan and hydroxyurea in chronic myelogenous leukemia: prolongation of survival by hydroxyurea. The German CML Study Group.

In a randomized multicenter study the influence of hydroxyurea versus busulfan on the duration of the chronic phase and on survival of chronic myelogenous leukemia (CML) was determined. In addition cross resistance and adverse reactions of the drugs were analyzed. From July 1983 to January 1991, 441 CML patients were randomized to receive hydroxyurea or busulfan. Of these, 90.7% were Philadelphia positive; 25.7% were low, 38.2% intermediate, and 36.2% high risk patients according to Sokal's score. The median survival of the busulfan treated Philadelphia-positive patients is 45.4 months and of the hydroxyurea group 58.2 months (P = .008). The survival advantage for the hydroxyurea treated patients is recognized in all risk groups. Sixty four patients reached therapy resistance before blast crisis and were crossed over to the alternative drug. The 23 patients with primary hydroxyurea had a median survival of 5.6 years, the 41 patients with primary busulfan therapy a median survival of 2.7 years (P = .02). Adverse reactions were less frequent with hydroxyurea with no severe adverse effects (lung fibrosis, long lasting bone marrow aplasia). The analysis of white blood cell counts in the course of treatment showed lower counts in the hydroxyurea patients. We conclude that hydroxyurea is superior to busulfan in therapy of CML in chronic phase and should be used as first line therapy. Busulfan may have a role as secondary therapy after hydroxyurea resistance or intolerance.

Blast Crisis↗
PubMed1984

Antifertility effect of busulfan and DL-6-(N-2-pipecolinomethyl)-5-hydroxy-indane maleate (PMHI) in coyotes (Canis Latrans ).

Antifertility effects of busulfan were evaluated using adult coyotes. In addition, antifertility effects of PMHI were evaluated in adult males. Adult males and females were alloted randomly to the following treatments: (1) untreated control, (2) a single oral dose of 3 mg busulfan/kg of body weight (BW) or (3) two oral doses of 3 mg busulfan/kg BW given nine days apart. The untreated males were used as controls in both experiments. Additional male coyotes were allotted randomly to PMHI treatments as follows: (1) a single oral dose of 2 mg PMHI/kg BW, or (2) two oral doses of 1 mg PMHI/kg BW given seven days apart. Blood samples were taken from females and serum analyzed for progesterone by radioimmunoassay. Males were hemicastrated (left testicle) 30 days after onset of treatment. The right testicle was removed 30 days later. Testes and epididymides were fixed in 10% buffered formalin and prepared for histologic examination. For females developing corpus luteum (CL), the maximum peak progesterone concentration for those given two doses of busulfan was less (P<0.05) than that for untreated controls and single-dose females (16.9, 22.4 and 26.3 ng/ml, respectively). The double treatment of busulfan prevented more females (4 of 10) from developing CL (P<0.08) than controls (0 of 7) or single-dose females (1 of 9). None of the busulfan-treated male coyotes had histologic evidence of spermatogenesis 60 days after the onset of treatment. The oral dose or doses of PMHI did not result in complete degeneration of seminiferous tubules. Busulfan given orally did not cause any adverse reactions, but orally administered PMHI often induced vomiting within 18 min after treatment. We conclude that busulfan is capable of affecting male and female reproductive parameters, but PMHI appears to have little effect on spermatogenesis in coyotes when given orally in a single- or a double-dose.

Journal Article↗
PubMed2005

Production of germline chimeric chickens following the administration of a busulfan emulsion.

Busulfan (1,4-butanediol dimethanesulfonate) was used to deplete endogenous germ cells for the enhanced production of chicken germline chimeras. Utilizing immunohistochemical identification of primordial gem cells (PGCs) in Stage 27 chicken embryos, two delivery formulations were compared relative to the degree of endogenous PGC depletion, a busulfan suspension (BS) and a solublized busulfan emulsion (SBE). Both busulfan treatments resulted in a significant reduction in PGCs when compared to controls. However, the SBE resulted in a more consistent and extensive depletion of PGCs than that observed with the BS treatment. Repopulation of SBE-treated embryos with exogenous PGCs resulted in a threefold increase of PGCs in Stage 27 embryos. Subsequently, germline chimeras were produced by the transfer of male gonadal PGCs from Barred Plymouth Rock embryos into untreated and SBE-treated White Leghorn embryos. Progeny testing of the presumptive chimeras with adult Barred Plymouth Rock chickens was performed to evaluate the efficiency of germline chimera production. The frequency of germline chimerism in SBE-treated recipients increased fivefold when compared to untreated recipients. The number of donor-derived offspring from the germline chimeras also increased eightfold following SBE-treatment of the recipient embryos. These results demonstrated that the administration of a busulfan emulsion into the egg yolk of unincubated eggs improved the depletion of endogenous PGCs in the embryo and enhanced the efficiency of germline chimera production.

Alkylating Agents↗
PubMed1993

Gas-chromatographic analysis of busulfan for therapeutic drug monitoring.

The development and validation of a gas chromatographic assay method for determination of total and free busulfan concentrations in human plasma for pharmacokinetic studies is reported. 1,6-Bis(methanesulfonyloxy)hexane, the internal standard, and a potential metabolite, 3-hydroxysulfolane, were synthesized. Plasma and plasma ultrafiltrate samples containing busulfan and internal standard were extracted with ethyl acetate and derivatized with 2,3,5,6-tetrafluorothiophenol prior to gas chromatographic determination. The 63Ni electron-capture detector provided a limit of detection of 0.0600 microgram/ml with a limit of quantitation of 0.100 microgram/ml busulfan in biological samples. Calibration curves were linear from 0.100 to 3.00 micrograms/ml in plasma (500 microliters) and 0.100 to 2.00 micrograms/ml in plasma ultrafiltrate (100 microliters). Extraction and derivatization yields ranged from 78.4% to 89.6% and 56.0% to 71.3%, respectively. Specificity of this assay for busulfan in the presence of its potential metabolites was demonstrated. Also, plasma samples containing co-administered drugs gave no response under these conditions. Clinical samples obtained following administration of a 1 mg/kg oral busulfan dose demonstrate the applicability of this method to analysis of total and free plasma concentrations.

Busulfan↗
PubMed1989

Late tissue-specific toxicity of total body irradiation and busulfan in a murine bone marrow transplant model.

Total body irradiation (TBI) and busulfan were compared for late effects in a murine model of bone marrow transplantation (BMT). Male C57BL/6 mice were given fractionated TBI or busulfan given in 4 equal daily doses followed by infusion of 10(7) syngeneic bone marrow cells. Total doses of 16.4 Gy TBI and 3.4 mg busulfan were chosen for their equivalence in inducing near complete engraftment of allogeneic marrow from donor mice of the LP strain. The two treatment groups had a late wave of mortality starting at about 80 weeks after transplantation. Specific tissue damage was manifested in bone marrow stem cells, splenic T-cell precursors, hair greying and cataract formation for both TBI and busulfan but to varying degrees. Severe nephrotoxicity and anemia were observed only after TBI. Although both busulfan and TBI kill early marrow stem cells and are effective preparative agents in bone marrow transplantation, their effects on other stem cell and organ systems are not similar. In addition, many of the injuries seen are late to occur. The delayed expression of injury deserves careful long-term evaluation of BMT recipients before the therapeutic potential of effective preparative regimens can be fully appreciated.

Animals↗
PubMed1994

Etoposide in combination with cyclophosphamide and total body irradiation or busulfan as conditioning for marrow transplantation in adults and children.

PURPOSE: In an attempt to intensify conditioning therapy for bone marrow transplantation of hematologic malignancies, a retrospective three center evaluation of escalating doses of etoposide added to cyclophosphamide and either total body irradiation or busulfan was undertaken. METHODS AND MATERIALS: Seventy-six patients who received etoposide (25-65 mg/kg) added to cyclophosphamide (60-120 mg/kg) and either total body irradiation (12.0-13.2 Gy) or busulfan (12-16 mg/kg) were evaluable for toxicity. Fifty-one of the evaluable patients received allogeneic transplants, while twenty-six received autologous transplants. A comparative analysis of toxicities according to conditioning regimen, donor source and etoposide dose was made. RESULTS: Similar toxicities were observed among the treatment groups with the exception of more frequent skin (p = 0.003) and life threatening hepatic toxicities (p = 0.01) in the busulfan treated patients. Life threatening or fatal toxicities were not influenced by donor source, either when analyzed by treatment group or etoposide dose. Etoposide at a dose of 60-65 mg/kg in combination with TBI and cyclophosphamide was associated with a significantly increased incidence of life threatening or fatal toxicities compared with a combination using a dose of 25-50 mg/kg (15 of 24 vs. 5 of 20; p = 0.013). The maximally tolerated dose of etoposide in combination with busulfan and cyclophosphamide cannot be definitively established in this analysis in part due to the heterogeneity of the patient population and treatment schemes. CONCLUSION: Although toxicities with bone marrow transplant preparative regimens containing etoposide in combination with cyclophosphamide and total body irradiation or busulfan were frequently severe, treatment related mortality risk was believed to be acceptably low.

Adolescent↗
PubMed1992

High-performance liquid chromatographic-mass spectrometric assay of busulfan in serum and cerebrospinal fluid.

A liquid chromatographic-mass spectrometric method has been developed to determine busulfan concentrations in the cerebrospinal fluid and serum of some children undergoing bone marrow autotransplantation. After two liquid-liquid extraction steps with dichloromethane on a biological matrix, the separation of busulfan was carried out by isocratic reversed-phase chromatography. The mass spectrometric system was operated in electron-impact mode. Principal ions at m/z 175, 111 and 79 were observed for busulfan, but only m/z 175 was chosen for the quantification of the analyte. The retention time of busulfan was 2.5 min. The detection limit of 100 ng/ml allowed the determination of cerebrospinal fluid and serum busulfan concentrations during the four days of high-dose (1 mg/kg) treatment prior to autotransplantation in five child patients.

Busulfan↗