Clarifying busulfan metabolism and drug interactions to support new therapeutic drug monitoring strategies: a comprehensive review

References

• Thomas ED. A history of allogeneic hematopoeitic cell transplanation. In: Appelbaum FR, Forman SJ, Negrin RS, et al., Ed. Thomas’ hematopoietic cell transplantation. 4th ed. Oxford, UK: Wiley-Blackwell; 2009. p. 3–7.
   Google Scholar
• Thomas ED, Buckner CD, Banaji M, et al. One hundred patients with acute leukemia treated by chemotherapy, total body irradiation, and allogeneic marrow transplantation. Blood. 1977;49:511–533.
   PubMed Web of Science ®Google Scholar
• Bredeson C, LeRademacher J, Kato K, et al. Prospective cohort study comparing intravenous busulfan to total body irradiation in hematopoietic cell transplantation. Blood. 2013;122:3871–3878.
   PubMed Web of Science ®Google Scholar
• Champlin RE. Busulfan or TBI: answer to an age-old question. Blood. 2013;122:3856–3857.
   PubMed Web of Science ®Google Scholar
• Ciurea SO, Andersson BS. Busulfan in hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2009;15:523–536.
   PubMed Web of Science ®Google Scholar
• Andersson BS, Thall PF, Madden T, et al. Busulfan systemic exposure relative to regimen-related toxicity and acute graft-versus-host disease: defining a therapeutic window for i.v. BuCy2 in chronic myelogenous leukemia. Biol Blood Marrow Transplant. 2002;8:477–485.
   PubMed Web of Science ®Google Scholar
• Vassal G, Deroussent A, Hartmann O, et al. Dose-dependent neurotoxicity of high-dose busulfan in children: a clinical and pharmacological study. Cancer Res. 1990;50:6203–6207.
   PubMed Web of Science ®Google Scholar
• McCune JS, Holmberg LA. Busulfan in hematopoietic stem cell transplant setting. Expert Opin Drug Metab Toxicol. 2009;5:957–969.
   PubMed Web of Science ®Google Scholar
• Buxton ILO. Pharmacokinetics and pharmacodynamics: the dynamics of drug absorption, distribution, metabolism, and elimination. In: Bruton LL, Ed. Goodman & Gilmans’s the pharmacological basis of therapeutics. 11th ed. New York, NY: McGraw-Hill Education; 2011. p. 1–39.
   Google Scholar
• Geddes M, Kangarloo SB, Naveed F, et al. High busulfan exposure is associated with worse outcomes in a daily i.v. busulfan and fludarabine allogeneic transplant regimen. Biol Blood Marrow Transplant. 2008;14:220–228.
   PubMed Web of Science ®Google Scholar
• Andersson BS, Thall PF, Valdez BC, et al. Fludarabine with pharmacokinetically-guided IV busulfan is superior to fixed-dose delivery in pretransplant conditioning of AML/MDS patients. Bone Marrow Transplant. 2017;52:580–587.
   PubMed Web of Science ®Google Scholar
• Bartelink IH, Lalmohamed A, van Reij EM, et al. Association of busulfan exposure with survival and toxicity after haemopoietic cell transplantation in children and young adults: a multicentre, retrospective cohort analysis. Lancet Haematol. 2016;3:526–536.
   PubMed Web of Science ®Google Scholar
• Trevisan DD, Silva JB, Oliveira HC, et al. Prevalence and clinical significance of potential drug-drug interaction in hematopoietic stem cell transplantation. Cancer Chemother Pharmacol. 2015;75:393–400.
   PubMed Web of Science ®Google Scholar
• Glotzbecker B, Duncan C, Alyea E 3rd, et al. Important drug interactions in hematopoietic stem cell transplantation: what every physician should know. Biol Blood Marrow Transplant. 2012;18:989–1006.
   PubMed Web of Science ®Google Scholar
• Guastaldi RB, Reis AM, Figueras A, et al. Prevalence of potential drug-drug interactions in bone marrow transplant patients. Int J Clin Pharm. 2011;33:1002–1009.
   PubMed Web of Science ®Google Scholar
• Hassan M, Andersson BS. Role of pharmacogenetics in busulfan/cyclophosphamide conditioning therapy prior to hematopoietic stem cell transplantation. Pharmacogenomics. 2013;14:75–87.
   PubMed Web of Science ®Google Scholar
• Myeleran (Busulfan) Prescribing Information, GlaxoSmith Kline (Greenville, NC, USA). 2002
   Google Scholar
• IV Busulfex (busulfan injection), Otsuka America Pharmaceutical Inc (Rockville, MD, USA). 2011
   Google Scholar
• Galaup A, Paci A. Pharmacology of dimethanesulfonate alkylating agents: busulfan and treosulfan. Expert Opin Drug Metab Toxicol. 2013;9:333–347.
   PubMed Web of Science ®Google Scholar
• Hartley JA, Fox BW. Cross-linking between histones and DNA following treatment with a series of dimethane sulphonate esters. Cancer Chemother Pharmacol. 1986;17:56–62.
   PubMed Web of Science ®Google Scholar
• DeLeve LD, Wang X. Role of oxidative stress and glutathione in busulfan toxicity in cultured murine hepatocytes. Pharmacology. 2000;60:143–154.
   PubMed Web of Science ®Google Scholar
• Peer CJ, Younis IR, Leonard SS, et al. Glutathione conjugation of busulfan produces a hydroxyl radical-trapping dehydroalanine metabolite. Xenobiotica. 2012;42:1170–1177.
   PubMed Web of Science ®Google Scholar
• Scian M, Atkins WM. The busulfan metabolite EdAG irreversibly glutathionylates glutaredoxins. Arch Biochem Biophys. 2015;583:96–104.
   PubMed Web of Science ®Google Scholar
• Younis IR, Elliott M, Peer CJ, et al. Dehydroalanine analog of glutathione: an electrophilic busulfan metabolite that binds to human glutathione S-transferase A1-1. J Pharmacol Exp Ther. 2008;327:770–776.
   PubMed Web of Science ®Google Scholar
• Grochow LB, Jones RJ, Brundrett RB, et al. Pharmacokinetics of busulfan: correlation with veno-occlusive disease in patients undergoing bone marrow transplantation. Cancer Chemother Pharmacol. 1989;25:55–61.
   PubMed Web of Science ®Google Scholar
• Hassan M, Ljungman P, Bolme P, et al. Busulfan bioavailability. Blood. 1994;84:2144–2150.
   PubMed Web of Science ®Google Scholar
• Hassan M, Oberg G, Bekassy AN, et al. Pharmacokinetics of high-dose busulphan in relation to age and chronopharmacology. Cancer Chemother Pharmacol. 1991;28:130–134.
   PubMed Web of Science ®Google Scholar
• Ehrsson H, Hassan M, Ehrnebo M, et al. Busulfan kinetics. Clin Pharmacol Ther. 1983;34:86–89.
   PubMed Web of Science ®Google Scholar
• Tran HT, Madden T, Petropoulos D, et al. Individualizing high-dose oral busulfan: prospective dose adjustment in a pediatric population undergoing allogeneic stem cell transplantation for advanced hematologic malignancies. Bone Marrow Transplant. 2000;26:463–470.
   PubMed Web of Science ®Google Scholar
• Krivoy N, Hoffer E, Lurie Y, et al. Busulfan use in hematopoietic stem cell transplantation: pharmacology, dose adjustment, safety and efficacy in adults and children. Curr Drug Saf. 2008;3:60–66.
   PubMedGoogle Scholar
• Bhagwatwar HP, Phadungpojna S, Chow DS, et al. Formulation and stability of busulfan for intravenous administration in high-dose chemotherapy. Cancer Chemother Pharmacol. 1996;37:401–408.
   PubMed Web of Science ®Google Scholar
• Madden T, de Lima M, Thapar N, et al. Pharmacokinetics of once-daily IV busulfan as part of pretransplantation preparative regimens: a comparison with an every 6-hour dosing schedule. Biol Blood Marrow Transplant. 2007;13:56–64.
   PubMed Web of Science ®Google Scholar
• Andersson BS, Kashyap A, Gian V, et al. Conditioning therapy with intravenous busulfan and cyclophosphamide (IV BuCy2) for hematologic malignancies prior to allogeneic stem cell transplantation: a phase II study. Biol Blood Marrow Transplant. 2002;8:145–154.
   PubMed Web of Science ®Google Scholar
• Hassan M, Ehrsson H, Smedmyr B, et al. Cerebrospinal fluid and plasma concentrations of busulfan during high-dose therapy. Bone Marrow Transplant. 1989;4:113–114.
   PubMed Web of Science ®Google Scholar
• Ehrsson H, Hassan M. Binding of busulfan to plasma proteins and blood cells. J Pharm Pharmacol. 1984;36:694–696.
   PubMed Web of Science ®Google Scholar
• Hassan M, Ehrsson H. Urinary metabolites of busulfan in the rat. Drug Metab Dispos. 1987;15:399–402.
   PubMed Web of Science ®Google Scholar
• Hassan M, Oberg G, Ehrsson H, et al. Pharmacokinetic and metabolic studies of high-dose busulphan in adults. Eur J Clin Pharmacol. 1989;36:525–530.
   PubMed Web of Science ®Google Scholar
• Gibbs JP, Czerwinski M, Slattery JT. Busulfan-glutathione conjugation catalyzed by human liver cytosolic glutathione S-transferases. Cancer Res. 1996;56:3678–3681.
   PubMed Web of Science ®Google Scholar
• Benson AM, Barretto PB. Effects of disulfiram, diethyldithiocarbamate, bisethylxanthogen, and benzyl isothiocyanate on glutathione transferase activities in mouse organs. Cancer Res. 1985;45:4219–4223.
   PubMed Web of Science ®Google Scholar
• Bouligand J, Deroussent A, Simonnard N, et al. Induction of glutathione synthesis explains pharmacodynamics of high-dose busulfan in mice and highlights putative mechanisms of drug interaction. Drug Metab Dispos. 2007;35:306–314.
   PubMed Web of Science ®Google Scholar
• Nation RL, Evans AM, Milne RW. Pharmacokinetic drug interactions with phenytoin (Part I). Clin Pharmacokinet. 1990;18:37–60.
   PubMed Web of Science ®Google Scholar
• Vassal G, Challine D, Koscielny S, et al. Chronopharmacology of high-dose busulfan in children. Cancer Res. 1993;53:1534–1537.
   PubMed Web of Science ®Google Scholar
• Inoue N, Imai K, Aimoto T. Circadian variation of hepatic glutathione S-transferase activities in the mouse. Xenobiotica. 1999;29:43–51.
   PubMed Web of Science ®Google Scholar
• Ferrell JM, Chiang JYL. Circadian rhythms in liver metabolism and disease. Acta Pharmaceutica Sinica B. 2015;5:113–122.
   PubMed Web of Science ®Google Scholar
• Hrushesky WJ. Circadian timing of cancer chemotherapy. Science. 1985;228:73–75.
   PubMed Web of Science ®Google Scholar
• Mross K, Haring B, Hollander N, et al. Comparison of 1-hour and 3-hours paclitaxel infusion pharmacokinetics: results from a randomized trial. Onkologie. 2002;25:503–508.
   PubMedGoogle Scholar
• Kangarloo SB, Naveed F, Ng ES, et al. Development and validation of a test dose strategy for once-daily i.v. busulfan: importance of fixed infusion rate dosing. Biol Blood Marrow Transplant. 2012;18:295–301.
   PubMed Web of Science ®Google Scholar
• Trams EG, Nadkarni MV, Dequattro V, et al. Dimethanesulphonoxybutane (Myleran): preliminary studies on distribution and metabolic fate in the rat. Biochem Pharmacol. 1959;2:7–16.
   Google Scholar
• Versace F, Uppugunduri CR, Krajinovic M, et al. A novel method for quantification of sulfolane (a metabolite of busulfan) in plasma by gas chromatography-tandem mass spectrometry. Anal Bioanal Chem. 2012;404:1831–1838.
   PubMed Web of Science ®Google Scholar
• El-Serafi I, Terelius Y, Twelkmeyer B, et al. Gas chromatographic-mass spectrometry method for the detection of busulphan and its metabolites in plasma and urine. J Chromatogr B Analyt Technol Biomed Life Sci. 2013;913-914:98–105.
   PubMed Web of Science ®Google Scholar
• Srivastava A, Poonkuzhali B, Shaji RV, et al. Glutathione S-transferase M1 polymorphism: a risk factor for hepatic venoocclusive disease in bone marrow transplantation. Blood. 2004;104:1574–1577.
   PubMed Web of Science ®Google Scholar
• Hassan M, Ehrsson H. Metabolism of 14C-busulfan in isolated perfused rat liver. Eur J Drug Metab Pharmacokinet. 1987;12:71–76.
   PubMed Web of Science ®Google Scholar
• Valdez BC, Hassan M, Andersson BS. Development of an assay for cellular efflux of pharmaceutically active agents and its relevance to understanding drug interactions. Exp Hematol. 2017;52: 65–71
   PubMed Web of Science ®Google Scholar
• Czerwinski M, Gibbs JP, Slattery JT. Busulfan conjugation by glutathione S-transferases alpha, mu, and pi. Drug Metab Dispos. 1996;24:1015–1019.
   PubMed Web of Science ®Google Scholar
• Gibbs JP, Yang JS, Slattery JT. Comparison of human liver and small intestinal glutathione S-transferase-catalyzed busulfan conjugation in vitro. Drug Metab Dispos. 1998;26:52–55.
   PubMed Web of Science ®Google Scholar
• Gibbs JP, Liacouras CA, Baldassano RN, et al. Up-regulation of glutathione S-transferase activity in enterocytes of young children. Drug Metab Dispos. 1999;27:1466–1469.
   PubMed Web of Science ®Google Scholar
• Cooper AJ, Younis IR, Niatsetskaya ZV, et al. Metabolism of the cysteine S-conjugate of busulfan involves a beta-lyase reaction. Drug Metab Dispos. 2008;36:1546–1552.
   PubMed Web of Science ®Google Scholar
• Baur X, Bittner C. Occupational obstructive airway diseases caused by the natural gas odorant tetrahydrothiophene–two case reports. Am J Ind Med. 2009;52:982–986.
   PubMed Web of Science ®Google Scholar
• Damani LA, Houdi AA. Cytochrome P-450 and FAD-monooxygenase mediated S- and N-oxygenations. Drug Metabol Drug Interact. 1988;6:235–244.
   PubMedGoogle Scholar
• Krueger SK, Williams DE. Mammalian flavin-containing monooxygenases: structure/function, genetic polymorphisms and role in drug metabolism. Pharmacol Ther. 2005;106:357–387.
   PubMed Web of Science ®Google Scholar
• Mozier NM, Hoffman JL. Biosynthesis and urinary excretion of methyl sulfonium derivatives of the sulfur mustard analog, 2-chloroethyl ethyl sulfide, and other thioethers. FASEB J. 1990;4:3329–3333.
   PubMed Web of Science ®Google Scholar
• Meganathan R, Schrementi J. Tetrahydrothiophene 1-oxide as an electron acceptor for escherichia coli. J Bacteriol. 1987;169:2862–2865.
   PubMed Web of Science ®Google Scholar
• Roberts JJ, Warwick GP. The mode of action of alkylating agents. III. The formation of 3-hydroxytetrahydrothiophene-1:1-dioxide from 1:4-dimethanesulphonyloxybutane (myleran), S-beta-L-alanyltetrahydrothiophenium mesylate, tetrahydrothiopene and tetrahydrothiophene-1:1-dioxide in the rat, rabbit and mouse. Biochem Pharmacol. 1961;6:217–227.
   Web of Science ®Google Scholar
• Ruppert PH, Dyer RS. Acute behavioral toxicity of sulfolane: influence of hypothermia. Toxicol Lett. 1985;28:111–116.
   PubMed Web of Science ®Google Scholar
• Andersen ME, Jones RA, Kurlansik L, et al. Sulfolane-induced convulsions in rodents. Res Commun Chem Pathol Pharmacol. 1976;15:571–580.
   PubMedGoogle Scholar
• Burdette LJ, Dyer RS. Sulfolane effects on audiogenic, pentylenetetrazol and afterdischarge seizure activity. Neurobehav Toxicol Teratol. 1986;8:621–626.
   PubMedGoogle Scholar
• Ghosh AK, Lee HY, Thompson WJ, et al. The development of cyclic sulfolanes as novel and high-affinity P2 ligands for HIV-1 protease inhibitors. J Med Chem. 1994;37:1177–1188.
   PubMed Web of Science ®Google Scholar
• Mohler FS, Gordon CJ. Thermoregulatory responses of the rabbit to central neural injections of sulfolane. Neurotoxicology. 1989;10:53–62.
   PubMed Web of Science ®Google Scholar
• Cole SP, Deeley RG. Transport of glutathione and glutathione conjugates by MRP1. Trends Pharmacol Sci. 2006;27:438–446.
   PubMed Web of Science ®Google Scholar
• Zaman GJ, Cnubben NH, van Bladeren PJ, et al. Transport of the glutathione conjugate of ethacrynic acid by the human multidrug resistance protein MRP. FEBS Lett. 1996;391:126–130.
   PubMed Web of Science ®Google Scholar
• Ploemen JH, van Ommen B, van Bladeren PJ. Inhibition of rat and human glutathione S-transferase isoenzymes by ethacrynic acid and its glutathione conjugate. Biochem Pharmacol. 1990;40:1631–1635.
   PubMed Web of Science ®Google Scholar
• Feit PW, Rastrup-Andersen N. 4-Methanesulfonyloxybutanol: hydrolysis of busulfan. J Pharm Sci. 1973;62:1007–1008.
   PubMed Web of Science ®Google Scholar
• Hassan M, Ehrsson H. Degradation of busulfan in aqueous solution. J Pharm Biomed Anal. 1986;4:95–101.
   PubMed Web of Science ®Google Scholar
• Reddy HR, Chandrasekhar N, Karigar CS. Gas chromatographic method for the quantitative determination of a hydrolytic degradation impurity in busulfan injectable products. J Chromatogr Sci. 2016;54:1475–1480.
   PubMed Web of Science ®Google Scholar
• Hudson RF, Timmis GM, Marshall RD. A physico-chemical investigation into the biological action of myleran and related sulphonic acid esters. Biochem Pharmacol. 1958;1:48–59.
   Web of Science ®Google Scholar
• Lenz D, Jubner M, Bender K, et al. Inhibition of 1,4-butanediol metabolism in human liver in vitro. Naunyn Schmiedebergs Arch Pharmacol. 2011;383:647–654.
   PubMed Web of Science ®Google Scholar
• Kazancioglu EA, Guney M, Senturk M, et al. Simple methanesulfonates are hydrolyzed by the sulfatase carbonic anhydrase activity. J Enzyme Inhib Med Chem. 2012;27:880–885.
   PubMed Web of Science ®Google Scholar
• Roberts JJ, Warwick GP. The mode of action of alkylating agents. II. Studies of the metabolism of myleran. The reaction of myleran with some naturally occurring thiols in vitro. Biochem Pharmacol. 1961;6:205–216.
   PubMed Web of Science ®Google Scholar
• Marchand DH, Remmel RP, Abdel-Monem MM. Biliary excretion of a glutathione conjugate of busulfan and 1,4-diiodobutane in the rat. Drug Metab Dispos. 1988;16:85–92.
   PubMed Web of Science ®Google Scholar
• Leonard SS, Xia C, Jiang BH, et al. Resveratrol scavenges reactive oxygen species and effects radical-induced cellular responses. Biochem Biophys Res Commun. 2003;309:1017–1026.
   PubMed Web of Science ®Google Scholar
• Kumar SS, Devasagayam TP, Bhushan B, et al. Scavenging of reactive oxygen species by chlorophyllin: an ESR study. Free Radic Res. 2001;35:563–574.
   PubMed Web of Science ®Google Scholar
• Baumhakel M, Kasel D, Rao-Schymanski RA, et al. Screening for inhibitory effects of antineoplastic agents on CYP3A4 in human liver microsomes. Int J Clin Pharmacol Ther. 2001;39:517–528.
   PubMed Web of Science ®Google Scholar
• Mostafa M, Chalvardjian K, Lami H, et al. Alteration in the capacities of carcinogen metabolizing system of mouse-livers during pretreatment with various antineoplastic agents. Oncol Rep. 1994;1:651–656.
   PubMed Web of Science ®Google Scholar
• Freireich EJ, Gehan EA, Rall DP, et al. Quantitative comparison of toxicity of anticancer agents in mouse, rat, hamster, dog, monkey, and man. Cancer Chemotherapy Reports Part 1. 1966;50:219–244.
   PubMedGoogle Scholar
• Yamazaki H, Inui Y, Yun CH, et al. Cytochrome P450 2E1 and 2A6 enzymes as major catalysts for metabolic activation of N-nitrosodialkylamines and tobacco-related nitrosamines in human liver microsomes. Carcinogenesis. 1992;13:1789–1794.
   PubMed Web of Science ®Google Scholar
• Abbasi N, Vadnais B, Knutson JA, et al. Pharmacogenetics of intravenous and oral busulfan in hematopoietic cell transplant recipients. J Clin Pharmacol. 2011;51:1429–1438.
   PubMed Web of Science ®Google Scholar
• Ansari M, Lauzon-Joset JF, Vachon MF, et al. Influence of GST gene polymorphisms on busulfan pharmacokinetics in children. Bone Marrow Transplant. 2010;45:261–267.
   PubMed Web of Science ®Google Scholar
• Ansari M, Rezgui MA, Theoret Y, et al. Glutathione S-transferase gene variations influence BU pharmacokinetics and outcome of hematopoietic SCT in pediatric patients. Bone Marrow Transplant. 2013;48:939–946.
   PubMed Web of Science ®Google Scholar
• Bonifazi F, Storci G, Bandini G, et al. Glutathione transferase-A2 S112T polymorphism predicts survival, transplant-related mortality, busulfan and bilirubin blood levels after allogeneic stem cell transplantation. Haematologica. 2014;99:172–179.
   PubMed Web of Science ®Google Scholar
• Elhasid R, Krivoy N, Rowe JM, et al. Influence of glutathione S-transferase A1, P1, M1, T1 polymorphisms on oral busulfan pharmacokinetics in children with congenital hemoglobinopathies undergoing hematopoietic stem cell transplantation. Pediatr Blood Cancer. 2010;55:1172–1179.
   PubMed Web of Science ®Google Scholar
• Gaziev J, Nguyen L, Puozzo C, et al. Novel pharmacokinetic behavior of intravenous busulfan in children with thalassemia undergoing hematopoietic stem cell transplantation: a prospective evaluation of pharmacokinetic and pharmacodynamic profile with therapeutic drug monitoring. Blood. 2010;115:4597–4604.
   PubMed Web of Science ®Google Scholar
• Goekkurt E, Stoehlmacher J, Stueber C, et al. Pharmacogenetic analysis of liver toxicity after busulfan/cyclophosphamide-based allogeneic hematopoietic stem cell transplantation. Anticancer Res. 2007;27:4377–4380.
   PubMed Web of Science ®Google Scholar
• Johnson L, Orchard PJ, Baker KS, et al. Glutathione S-transferase A1 genetic variants reduce busulfan clearance in children undergoing hematopoietic cell transplantation. J Clin Pharmacol. 2008;48:1052–1062.
   PubMed Web of Science ®Google Scholar
• Kim I, Keam B, Lee KH, et al. Glutathione S-transferase A1 polymorphisms and acute graft-vs.-host disease in HLA-matched sibling allogeneic hematopoietic stem cell transplantation. Clin Transplant. 2007;21:207–213.
   PubMed Web of Science ®Google Scholar
• Kim SD, Lee JH, Hur EH, et al. Influence of GST gene polymorphisms on the clearance of intravenous busulfan in adult patients undergoing hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2011;17:1222–1230.
   PubMed Web of Science ®Google Scholar
• Krivoy N, Zuckerman T, Elkin H, et al. Pharmacokinetic and pharmacogenetic analysis of oral busulfan in stem cell transplantation: prediction of poor drug metabolism to prevent drug toxicity. Curr Drug Saf. 2012;7:211–217.
   PubMedGoogle Scholar
• Kusama M, Kubota T, Matsukura Y, et al. Influence of glutathione S-transferase A1 polymorphism on the pharmacokinetics of busulfan. Clin Chim Acta: Int J Clin Chem. 2006;368:93–98.
   PubMed Web of Science ®Google Scholar
• Ten Brink MH, Swen JJ, Bohringer S, et al. Exploratory analysis of 1936 SNPs in ADME genes for association with busulfan clearance in adult hematopoietic stem cell recipients. Pharmacogenet Genomics. 2013;23:675–683.
   PubMed Web of Science ®Google Scholar
• ten Brink MH, van Bavel T, Swen JJ, et al. Effect of genetic variants GSTA1 and CYP39A1 and age on busulfan clearance in pediatric patients undergoing hematopoietic stem cell transplantation. Pharmacogenomics. 2013;14:1683–1690.
   PubMed Web of Science ®Google Scholar
• Ten Brink MH, Wessels JA, den Hartigh J, et al. Effect of genetic polymorphisms in genes encoding GST isoenzymes on BU pharmacokinetics in adult patients undergoing hematopoietic SCT. Bone Marrow Transplant. 2012;47:190–195.
   PubMed Web of Science ®Google Scholar
• Zwaveling J, Press RR, Bredius RG, et al. Glutathione S-transferase polymorphisms are not associated with population pharmacokinetic parameters of busulfan in pediatric patients. Ther Drug Monit. 2008;30:504–510.
   PubMed Web of Science ®Google Scholar
• Huezo-Diaz P, Uppugunduri CR, Tyagi AK, et al. Pharmacogenetic aspects of drug metabolizing enzymes in busulfan based conditioning prior to allogenic hematopoietic stem cell transplantation in children. Curr Drug Metab. 2014;15:251–264.
   PubMed Web of Science ®Google Scholar
• Geller RB, Saral R, Piantadosi S, et al. Allogeneic bone marrow transplantation after high-dose busulfan and cyclophosphamide in patients with acute nonlymphocytic leukemia. Blood. 1989;73:2209–2218.
   PubMed Web of Science ®Google Scholar
• Tetlow N, Board PG. Functional polymorphism of human glutathione transferase A2. Pharmacogenetics. 2004;14:111–116.
   PubMedGoogle Scholar
• Valdez BC, Li Y, Murray D, et al. Differential effects of histone deacetylase inhibitors on cellular drug transporters and their implications for using epigenetic modifiers in combination chemotherapy. Oncotarget. 2016;7:63829–63838.
   PubMed Web of Science ®Google Scholar
• Uppugunduri CR, Rezgui MA, Diaz PH, et al. The association of cytochrome P450 genetic polymorphisms with sulfolane formation and the efficacy of a busulfan-based conditioning regimen in pediatric patients undergoing hematopoietic stem cell transplantation. Pharmacogenomics J. 2014;14:263–271.
   PubMed Web of Science ®Google Scholar
• de Jonge ME, Huitema AD, Rodenhuis S, et al. Clinical pharmacokinetics of cyclophosphamide. Clin Pharmacokinet. 2005;44:1135–1164.
   PubMed Web of Science ®Google Scholar
• Lorbek G, Lewinska M, Rozman D. Cytochrome P450s in the synthesis of cholesterol and bile acids–from mouse models to human diseases. Febs J. 2012;279:1516–1533.
   PubMed Web of Science ®Google Scholar
• Uchiyama T, Kanno H, Ishitani K, et al. An SNP in CYP39A1 is associated with severe neutropenia induced by docetaxel. Cancer Chemother Pharmacol. 2012;69:1617–1624.
   PubMed Web of Science ®Google Scholar
• Kim DH, Park JY, Sohn SK, et al. The association between multidrug resistance-1 gene polymorphisms and outcomes of allogeneic HLA-identical stem cell transplantation. Haematologica. 2006;91:848–851.
   PubMed Web of Science ®Google Scholar
• Sweiss K, Patel P, Rondelli D. Deferasirox increases BU blood concentrations. Bone Marrow Transplant. 2012;47:315–316.
   PubMed Web of Science ®Google Scholar
• Carter J, Yeh RF, Braunschweig I, et al. Unreported use of an herbal supplement resulting in decreased clearance of intravenous busulfan in a patient undergoing auto-SCT. Bone Marrow Transplant. 2014;49:313–314.
   PubMed Web of Science ®Google Scholar
• de Castro FA, Lanchote VL, Voltarelli JC, et al. Influence of fludarabine on the pharmacokinetics of oral busulfan during pretransplant conditioning for hematopoietic stem cell transplantation. J Clin Pharmacol. 2013;53:1205–1211.
   PubMed Web of Science ®Google Scholar
• Perkins JB, Kim J, Anasetti C, et al. Maximally tolerated busulfan systemic exposure in combination with fludarabine as conditioning before allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2012;18:1099–1107.
   PubMed Web of Science ®Google Scholar
• Yeh RF, Pawlikowski MA, Blough DK, et al. Accurate targeting of daily intravenous busulfan with 8-hour blood sampling in hospitalized adult hematopoietic cell transplant recipients. Biol Blood Marrow Transplant. 2012;18:265–272.
   PubMed Web of Science ®Google Scholar
• Buggia I, Zecca M, Alessandrino EP, et al. Itraconazole can increase systemic exposure to busulfan in patients given bone marrow transplantation. GITMO (Gruppo Italiano Trapianto di Midollo Osseo). Anticancer Res. 1996;16:2083–2088.
   PubMed Web of Science ®Google Scholar
• Hassan M, Svensson JO, Nilsson C, et al. Ketobemidone may alter busulfan pharmacokinetics during high-dose therapy. Ther Drug Monit. 2000;22:383–385.
   PubMed Web of Science ®Google Scholar
• Gulbis AM, Culotta KS, Jones RB, et al. Busulfan and metronidazole: an often forgotten but significant drug interaction. Ann Pharmacother. 2010;45:e39.
   Google Scholar
• Chung H, Yu KS, Hong KT, et al. A significant influence of metronidazole on busulfan pharmacokinetics: a case report of therapeutic drug monitoring. Ther Drug Monit. 2017;39:208–210.
   PubMed Web of Science ®Google Scholar
• Nilsson C, Aschan J, Hentschke P, et al. The effect of metronidazole on busulfan pharmacokinetics in patients undergoing hematopoietic stem cell transplantation. Bone Marrow Transplant. 2003;31:429–435.
   PubMed Web of Science ®Google Scholar
• Hassan M, Oberg G, Bjorkholm M, et al. Influence of prophylactic anticonvulsant therapy on high-dose busulphan kinetics. Cancer Chemother Pharmacol. 1993;33:181–186.
   PubMed Web of Science ®Google Scholar
• Nguyen L, Leger F, Lennon S, et al. Intravenous busulfan in adults prior to haematopoietic stem cell transplantation: a population pharmacokinetic study. Cancer Chemother Pharmacol. 2006;57:191–198.
   PubMed Web of Science ®Google Scholar
• Zwaveling J, Bredius RG, Cremers SC, et al. Intravenous busulfan in children prior to stem cell transplantation: study of pharmacokinetics in association with early clinical outcome and toxicity. Bone Marrow Transplant. 2005;35:17–23.
   PubMed Web of Science ®Google Scholar
• Bensinger WI, Buckner CD, Lilleby K, et al. Dose escalation of busulfan with pentoxifylline and ciprofloxacin in patients with breast cancer undergoing autologous transplants. Oncology. 2004;67:368–375.
   PubMed Web of Science ®Google Scholar
• Carreras E, Cahn JY, Puozzo C, et al. Influence on Busilvex pharmacokinetics of clonazepam compared to previous phenytoin historical data. Anticancer Res. 2010;30:2977–2984.
   PubMed Web of Science ®Google Scholar
• Andersson BS, de Lima M, Thall PF, et al. Once daily i.v. busulfan and fludarabine (i.v. Bu-Flu) compares favorably with i.v. busulfan and cyclophosphamide (i.v. BuCy2) as pretransplant conditioning therapy in AML/MDS. Biol Blood Marrow Transplant. 2008;14:672–684.
   PubMed Web of Science ®Google Scholar
• Almog S, Kurnik D, Shimoni A, et al. Linearity and stability of intravenous busulfan pharmacokinetics and the role of glutathione in busulfan elimination. Biol Blood Marrow Transplant. 2011;17:117–123.
   PubMed Web of Science ®Google Scholar
• Bonin M, Pursche S, Bergeman T, et al. F-ara-A pharmacokinetics during reduced-intensity conditioning therapy with fludarabine and busulfan. Bone Marrow Transplant. 2007;39:201–206.
   PubMed Web of Science ®Google Scholar
• Chan KW, Mullen CA, Worth LL, et al. Lorazepam for seizure prophylaxis during high-dose busulfan administration. Bone Marrow Transplant. 2002;29:963–965.
   PubMed Web of Science ®Google Scholar
• Hamidieh AA, Hamedani R, Hadjibabaie M, et al. Oral lorazepam prevents seizure during high-dose busulfan in children undergoing hematopoietic stem cell transplantation: a prospective study. Pediatr Hematol Oncol. 2010;27:529–533.
   PubMed Web of Science ®Google Scholar
• Sjoo F, Aschan J, Barkholt L, et al. N-acetyl-L-cysteine does not affect the pharmacokinetics or myelosuppressive effect of busulfan during conditioning prior to allogeneic stem cell transplantation. Bone Marrow Transplant. 2003;32:349–354.
   PubMed Web of Science ®Google Scholar
• McGill MR, Jaeschke H. Metabolism and disposition of acetaminophen: recent advances in relation to hepatotoxicity and diagnosis. Pharm Res. 2013;30:2174–2187.
   PubMed Web of Science ®Google Scholar
• Coles B, Wilson I, Wardman P, et al. The spontaneous and enzymatic reaction of N-acetyl-p-benzoquinonimine with glutathione: a stopped-flow kinetic study. Arch Biochem Biophys. 1988;264:253–260.
   PubMed Web of Science ®Google Scholar
• Walker V, Mills GA, Anderson ME, et al. The acetaminophen metabolite N-acetyl-p-benzoquinone imine (NAPQI) inhibits glutathione synthetase in vitro; a clue to the mechanism of 5-oxoprolinuric acidosis? Xenobiotica. 2017;47:164–175.
   PubMed Web of Science ®Google Scholar
• Granfors MT, Backman JT, Neuvonen M, et al. Ciprofloxacin greatly increases concentrations and hypotensive effect of tizanidine by inhibiting its cytochrome P450 1A2-mediated presystemic metabolism. Clin Pharmacol Ther. 2004;76:598–606.
   PubMed Web of Science ®Google Scholar
• Dautrey S, Felice K, Petiet A, et al. Active intestinal elimination of ciprofloxacin in rats: modulation by different substrates. Br J Pharmacol. 1999;127:1728–1734.
   PubMed Web of Science ®Google Scholar
• Haslam IS, Wright JA, O’Reilly DA, et al. Intestinal ciprofloxacin efflux: the role of breast cancer resistance protein (ABCG2). Drug Metab Dispos. 2011;39:2321–2328.
   PubMed Web of Science ®Google Scholar
• Charasson V, Haaz MC, Robert J. Determination of drug interactions occurring with the metabolic pathways of irinotecan. Drug Metab Dispos. 2002;30:731–733.
   PubMed Web of Science ®Google Scholar
• Pacifici GM, Gustafsson LL, Sawe J, et al. Metabolic interaction between morphine and various benzodiazepines. Acta Pharmacol Toxicol (Copenh). 1986;58:249–252.
   PubMedGoogle Scholar
• Seree EJ, Pisano PJ, Placidi M, et al. Identification of the human and animal hepatic cytochromes P450 involved in clonazepam metabolism. Fundam Clin Pharmacol. 1993;7:69–75.
   PubMed Web of Science ®Google Scholar
• EXJADE (deferasirox) tablets, for oral suspension, Novartis Pharmaceuticals (East Hanover, NJ, USA). 2013
   Google Scholar
• Jung F, Richardson TH, Raucy JL, et al. Diazepam metabolism by cDNA-expressed human 2C P450s: identification of P4502C18 and P4502C19 as low K(M) diazepam N-demethylases. Drug Metab Dispos. 1997;25:133–139.
   PubMed Web of Science ®Google Scholar
• Kenworthy KE, Clarke SE, Andrews J, et al. Multisite kinetic models for CYP3A4: simultaneous activation and inhibition of diazepam and testosterone metabolism. Drug Metab Dispos. 2001;29:1644–1651.
   PubMed Web of Science ®Google Scholar
• Yang AK, He SM, Liu L, et al. Herbal interactions with anticancer drugs: mechanistic and clinical considerations. Curr Med Chem. 2010;17:1635–1678.
   PubMed Web of Science ®Google Scholar
• Guo Z, Smith TJ, Wang E, et al. Effects of phenethyl isothiocyanate, a carcinogenesis inhibitor, on xenobiotic-metabolizing enzymes and nitrosamine metabolism in rats. Carcinogenesis. 1992;13:2205–2210.
   PubMed Web of Science ®Google Scholar
• Lin SC, Chung TC, Lin CC, et al. Hepatoprotective effects of Arctium lappa on carbon tetrachloride- and acetaminophen-induced liver damage. Am J Chin Med. 2000;28:163–173.
   PubMed Web of Science ®Google Scholar
• Nivoix Y, Leveque D, Herbrecht R, et al. The enzymatic basis of drug-drug interactions with systemic triazole antifungals. Clin Pharmacokinet. 2008;47:779–792.
   PubMed Web of Science ®Google Scholar
• Gandhi V, Plunkett W. Cellular and clinical pharmacology of fludarabine. Clin Pharmacokinet. 2002;41:93–103.
   PubMed Web of Science ®Google Scholar
• Lempers VJ, van den Heuvel JJ, Russel FG, et al. Inhibitory potential of antifungal drugs on ATP-binding cassette transporters P-Glycoprotein, MRP1 to MRP5, BCRP, and BSEP. Antimicrob Agents Chemother. 2016;60:3372–3379.
   PubMed Web of Science ®Google Scholar
• Vermeer LM, Isringhausen CD, Ogilvie BW, et al. Evaluation of ketoconazole and its alternative clinical CYP3A4/5 inhibitors as inhibitors of drug transporters: the in vitro effects of ketoconazole, ritonavir, clarithromycin, and itraconazole on 13 clinically-relevant drug transporters. Drug Metab Dispos. 2016;44:453–459.
   PubMed Web of Science ®Google Scholar
• Isoherranen N, Kunze KL, Allen KE, et al. Role of itraconazole metabolites in CYP3A4 inhibition. Drug Metab Dispos. 2004;32:1121–1131.
   PubMed Web of Science ®Google Scholar
• Yasar U, Annas A, Svensson JO, et al. Ketobemidone is a substrate for cytochrome P4502C9 and 3A4, but not for P-glycoprotein. Xenobiotica. 2005;35:785–796.
   PubMed Web of Science ®Google Scholar
• Meacham RH Jr., Sisenwine SF, Liu AL, et al. Inhibition of ciramadol glucuronidation by benzodiazepines. Drug Metab Dispos. 1986;14:430–436.
   PubMed Web of Science ®Google Scholar
• Uchaipichat V, Suthisisang C, Miners JO. The glucuronidation of R- and S-lorazepam: human liver microsomal kinetics, UDP-glucuronosyltransferase enzyme selectivity, and inhibition by drugs. Drug Metab Dispos. 2013;41:1273–1284.
   PubMed Web of Science ®Google Scholar
• Pearce RE, Cohen-Wolkowiez M, Sampson MR, et al. The role of human cytochrome P450 enzymes in the formation of 2-hydroxymetronidazole: CYP2A6 is the high affinity (Low Km) catalyst. Drug Metab Dispos. 2013;41:1686–1694.
   PubMed Web of Science ®Google Scholar
• Edwards JA, Price J. Metronidazole and human alcohol dehydrogenase. Nature. 1967;214:190–191.
   PubMed Web of Science ®Google Scholar
• Meister A. Glutathione metabolism and its selective modification. J Biol Chem. 1988;263:17205–17208.
   PubMed Web of Science ®Google Scholar
• Yamauchi A, Ueda N, Hanafusa S, et al. Tissue distribution of and species differences in deacetylation of N-acetyl-L-cysteine and immunohistochemical localization of acylase I in the primate kidney. J Pharm Pharmacol. 2002;54:205–212.
   PubMed Web of Science ®Google Scholar
• Potschka H, Fedrowitz M, Loscher W. Multidrug resistance protein MRP2 contributes to blood-brain barrier function and restricts antiepileptic drug activity. J Pharmacol Exp Ther. 2003;306:124–131.
   PubMed Web of Science ®Google Scholar
• Giancarlo GM, Venkatakrishnan K, Granda BW, et al. Relative contributions of CYP2C9 and 2C19 to phenytoin 4-hydroxylation in vitro: inhibition by sulfaphenazole, omeprazole, and ticlopidine. Eur J Clin Pharmacol. 2001;57:31–36.
   PubMed Web of Science ®Google Scholar
• Akan H, Antia VP, Kouba M, et al. Preventing invasive fungal disease in patients with haematological malignancies and the recipients of haematopoietic stem cell transplantation: practical aspects. J Antimicrob Chemother. 2013;68(Suppl 3):iii5–iii16.
   PubMed Web of Science ®Google Scholar
• Jaschonek K, Steinhilber D, Einsele H, et al. 5-Lipoxygenase inhibition by antifungal azole derivatives: new tools for immunosuppression? Eicosanoids. 1989;2:189–190.
   PubMedGoogle Scholar
• Samuelsson B, Dahlen SE, Lindgren JA, et al. Leukotrienes and lipoxins: structures, biosynthesis, and biological effects. Science. 1987;237:1171–1176.
   PubMed Web of Science ®Google Scholar
• Kim KA, Park JY. Effect of metronidazole on the pharmacokinetics of fexofenadine, a P-glycoprotein substrate, in healthy male volunteers. Eur J Clin Pharmacol. 2010;66:721–725.
   PubMed Web of Science ®Google Scholar
• Larsson P, Cybulski W, Tjalve H. Binding of 3H-metronidazole in olfactory, respiratory and alimentary epithelia in rats. Pharmacol Toxicol. 1997;81:65–73.
   PubMedGoogle Scholar
• Styler MJ, Crilley P, Biggs J, et al. Hepatic dysfunction following busulfan and cyclophosphamide myeloablation: a retrospective, multicenter analysis. Bone Marrow Transplant. 1996;18:171–176.
   PubMed Web of Science ®Google Scholar
• Bondesson U, Hartvig P, Danielsson B. Quantitative determination of the urinary excretion of ketobemidone and four of its metabolites after intravenous and oral administration in man. Drug Metab Dispos. 1981;9:376–380.
   PubMed Web of Science ®Google Scholar
• Al-Shurbaji A, Sawe J. The pharmacokinetics of ketobemidone are not affected by CYP2D6 or CYP2C19 phenotype. Eur J Clin Pharmacol. 2002;57:877–881.
   PubMed Web of Science ®Google Scholar
• Fitzsimmons WE, Ghalie R, Kaizer H. Anticonvulsants and busulfan. Ann Intern Med. 1990;112:552–553.
   PubMed Web of Science ®Google Scholar
• de Lima M, Couriel D, Thall PF, et al. Once-daily intravenous busulfan and fludarabine: clinical and pharmacokinetic results of a myeloablative, reduced-toxicity conditioning regimen for allogeneic stem cell transplantation in AML and MDS. Blood. 2004;104:857–864.
   PubMed Web of Science ®Google Scholar
• Hassan M, Ljungman P, Ringden O, et al. The effect of busulphan on the pharmacokinetics of cyclophosphamide and its 4-hydroxy metabolite: time interval influence on therapeutic efficacy and therapy-related toxicity. Bone Marrow Transplant. 2000;25:915–924.
   PubMed Web of Science ®Google Scholar
• McCune JS, Batchelder A, Deeg HJ, et al. Cyclophosphamide following targeted oral busulfan as conditioning for hematopoietic cell transplantation: pharmacokinetics, liver toxicity, and mortality. Biol Blood Marrow Transplant. 2007;13:853–862.
   PubMed Web of Science ®Google Scholar
• Rezvani AR, McCune JS, Storer BE, et al. Cyclophosphamide followed by intravenous targeted busulfan for allogeneic hematopoietic cell transplantation: pharmacokinetics and clinical outcomes. Biol Blood Marrow Transplant. 2013;19:1033–1039.
   PubMed Web of Science ®Google Scholar
• Cantoni N, Gerull S, Heim D, et al. Order of application and liver toxicity in patients given BU and CY containing conditioning regimens for allogeneic hematopoietic SCT. Bone Marrow Transplant. 2011;46:344–349.
   PubMed Web of Science ®Google Scholar
• Kerbauy FR, Tirapelli B, Akabane H, et al. The effect of administration order of BU and CY on toxicity in hematopoietic SCT in humans. Bone Marrow Transplant. 2009;43:883–885.
   PubMed Web of Science ®Google Scholar
• Dockham PA, Sreerama L, Sladek NE. Relative contribution of human erythrocyte aldehyde dehydrogenase to the systemic detoxification of the oxazaphosphorines. Drug Metab Dispos. 1997;25:1436–1441.
   PubMed Web of Science ®Google Scholar
• Dourthe ME, Ternes N, Gajda D, et al. Busulfan-Melphalan followed by autologous stem cell transplantation in patients with high-risk neuroblastoma or Ewing sarcoma: an exposed-unexposed study evaluating the clinical impact of the order of drug administration. Bone Marrow Transplant. 2016;51:1265–1267.
   PubMed Web of Science ®Google Scholar
• Bouligand J, Richard C, Valteau-Couanet D, et al. Iron overload exacerbates busulfan-melphalan toxicity through a pharmacodynamic interaction in mice. Pharm Res. 2016;33:1913–1922.
   PubMed Web of Science ®Google Scholar
• Dirven HA, van Ommen B, van Bladeren PJ. Glutathione conjugation of alkylating cytostatic drugs with a nitrogen mustard group and the role of glutathione S-transferases. Chem Res Toxicol. 1996;9:351–360.
   PubMed Web of Science ®Google Scholar
• Bouligand J, Boland I, Valteau-Couanet D, et al. In children and adolescents, the pharmacodynamics of high-dose busulfan is dependent on the second alkylating agent used in the combined regimen (melphalan or thiotepa). Bone Marrow Transplant. 2003;32:979–986.
   PubMed Web of Science ®Google Scholar
• Sheth S. Iron chelation: an update. Curr Opin Hematol. 2014;21:179–185.
   PubMed Web of Science ®Google Scholar
• Bartelink IH, Bredius RG, Ververs TT, et al. Once-daily intravenous busulfan with therapeutic drug monitoring compared to conventional oral busulfan improves survival and engraftment in children undergoing allogeneic stem cell transplantation. Biol Blood Marrow Transplant. 2008;14:88–98.
   PubMed Web of Science ®Google Scholar
• Grochow LB. Busulfan disposition: the role of therapeutic monitoring in bone marrow transplantation induction regimens. Semin Oncol. 1993;20: 18–25. quiz 26.
   PubMed Web of Science ®Google Scholar
• Bostrom B, Enockson K, Johnson A, et al. Plasma pharmacokinetics of high-dose oral busulfan in children and adults undergoing bone marrow transplantation. Pediatr Transplant. 2003;7(Suppl 3):12–18.
   PubMed Web of Science ®Google Scholar
• Bartelink IH, van Kesteren C, Boelens JJ, et al. Predictive performance of a busulfan pharmacokinetic model in children and young adults. Ther Drug Monit. 2012;34:574–583.
   PubMed Web of Science ®Google Scholar
• Nguyen L, Fuller D, Lennon S, et al. I.V. busulfan in pediatrics: a novel dosing to improve safety/efficacy for hematopoietic progenitor cell transplantation recipients. Bone Marrow Transplant. 2004;33:979–987.
   PubMed Web of Science ®Google Scholar
• Paci A, Vassal G, Moshous D, et al. Pharmacokinetic behavior and appraisal of intravenous busulfan dosing in infants and older children: the results of a population pharmacokinetic study from a large pediatric cohort undergoing hematopoietic stem-cell transplantation. Ther Drug Monit. 2012;34:198–208.
   PubMed Web of Science ®Google Scholar
• Bartelink IH, Boelens JJ, Bredius RG, et al. Body weight-dependent pharmacokinetics of busulfan in paediatric haematopoietic stem cell transplantation patients: towards individualized dosing. Clin Pharmacokinet. 2012;51:331–345.
   PubMed Web of Science ®Google Scholar
• Slattery JT, Risler LJ. Therapeutic monitoring of busulfan in hematopoietic stem cell transplantation. Ther Drug Monit. 1998;20:543–549.
   PubMed Web of Science ®Google Scholar