The importance of drug metabolites synthesis: the case-study of cardiotoxic anticancer drugs

References

• Abraham TW, Kalman TI, Mcintee EJ, Wagner CR. (1996). Synthesis and biological activity of aromatic amino acid phosphoramidates of 5-fluoro-2′-deoxyuridine and 1-β-arabinofuranosylcytosine: evidence of phosphoramidase activity. J Med Chem 39:4569–4575.
   PubMed Web of Science ®Google Scholar
• Aminkeng F, Bhavsar AP, Visscher H, et al. (2015). A coding variant in RARG confers susceptibility to anthracycline-induced cardiotoxicity in childhood cancer. Nat Genet 47:1079–1084.
   PubMed Web of Science ®Google Scholar
• Ang C, Kornbluth M, Thirlwell MP, Rajan RD. (2010). Capecitabine-induced cardiotoxicity: Case report and review of the literature. Curr Oncol 17:59–63.
   PubMed Web of Science ®Google Scholar
• Anon. (2006). Nexavar: INN-Sorafenib [last accessed 5 May 2016].
   Google Scholar
• Anon. (2015). Nexavar. Summary of product characteristics [last accessed 5 May 2016].
   Google Scholar
• Arellano M, Malet-Martino M, Martino R, Gires P. (1998). The anti-cancer drug 5-fluorouracil is metabolized by the isolated perfused rat liver and in rats into highly toxic fluoroacetate. Br J Cancer 77:79–86.
   PubMed Web of Science ®Google Scholar
• Asha S, Vidyavathi M. (2010). Role of human liver microsomes in in vitro metabolism of drugs—A review. Appl Biochem Biotechnol 160:1699–1722.
   PubMed Web of Science ®Google Scholar
• Baillie TA, Cayen MN, Fouda H, et al. (2002). Drug metabolites in safety testing. Toxicol Appl Pharmacol 182:188–196.
   PubMed Web of Science ®Google Scholar
• Balis FM, Holcenberg JS, Bleyer WA. (1983). Clinical pharmacokinetics of commonly used anticancer drugs. Clin Pharmacokinet 8:202–232.
   PubMed Web of Science ®Google Scholar
• Batra VK, Morrison JA, Woodward DL, et al. (1986). Pharmacokinetics of mitoxantrone in man and laboratory animals. Drug Metab Rev 17:311–329.
   PubMed Web of Science ®Google Scholar
• Bjornsson TD, Callaghan JT, Einolf HJ, et al. (2003). The conduct of in vitro and in vivo drug–drug interaction studies: A pharmaceutical research and manufacturers of America (PhRMA) perspective. Drug Metab Dispos 31:815–832.
   PubMed Web of Science ®Google Scholar
• Blanz J, Mewes K, Ehninger G, et al. (1991). Evidence for oxidative activation of mitoxantrone in human, pig, and rat. Drug Metab Dispos 19:871–880.
   PubMed Web of Science ®Google Scholar
• Boucek RJ Jr, Olson RD, Brenner DE, et al. (1987). The major metabolite of doxorubicin is a potent inhibitor of membrane-associated ion pumps: A correlative study of cardiac muscle with isolated membrane fractions. J Biol Chem 262:15851–15856.
   PubMed Web of Science ®Google Scholar
• Brandon EFA, Raap CD, Meijerman I, et al. (2003). An update on in vitro test methods in human hepatic drug biotransformation research: Pros and cons. Toxicol Appl Pharmacol 189:233–246.
   PubMed Web of Science ®Google Scholar
• Burridge PW, Li YF, Matsa E, et al. (2016). Human induced pluripotent stem cell-derived cardiomyocytes recapitulate the predilection of breast cancer patients to doxorubicin-induced cardiotoxicity. Nat Med 22:547–556.
   PubMed Web of Science ®Google Scholar
• Caballero J, Muñoz C, Alzate-Morales JH, et al. (2012). Synthesis, in silico, in vitro, and in vivo investigation of 5-[11C]methoxy-substituted sunitinib, a tyrosine kinase inhibitor of VEGFR-2. Eur J Med Chem 58:272–280.
   PubMed Web of Science ®Google Scholar
• Chawla SP, Chua VS, Hendifar AF, et al. (2015). A phase 1B/2 study of aldoxorubicin in patients with soft tissue sarcoma. Cancer 121:570–579.
   PubMed Web of Science ®Google Scholar
• Chiccarelli FS, Morrison JA, Cosulich DB, et al. (1986). Identification of human urinary mitoxantrone metabolites. Cancer Res 46:4858–4861.
   PubMed Web of Science ®Google Scholar
• Chu TF, Rupnick MA, Kerkela R, et al. (2007). Cardiotoxicity associated with tyrosine kinase inhibitor sunitinib. Lancet 370:2011–2019.
   PubMed Web of Science ®Google Scholar
• Connors TA, Cox PJ, Farmer PB, et al. (1974). Some studies of the active intermediates formed in the microsomal metabolism of cyclophosphamide and isophosphamide. Biochem Pharmacol 23:115–129.
   PubMed Web of Science ®Google Scholar
• Costa VM, Carvalho F, Duarte JA, et al. (2013). The heart as a target for xenobiotic toxicity: The cardiac susceptibility to oxidative stress. Chem Res Toxicol 26:1285–1311.
   PubMed Web of Science ®Google Scholar
• Crombag MRBS, Joerger M, Thürlimann B, et al. (2016). Pharmacokinetics of selected anticancer drugs in elderly cancer patients: Focus on breast cancer. Cancers 8:1–22.
   Web of Science ®Google Scholar
• Daumar P, Decombat C, Chezal J-M, et al. (2011). Design, synthesis and in vitro drug release investigation of new potential 5-FU prodrugs. Eur J Med Chem 46:2867–2879.
   PubMed Web of Science ®Google Scholar
• De Jonge ME, Huitema ADR, Rodenhuis S, Beijnen JH. (2005). Clinical pharmacokinetics of cyclophosphamide. Clin Pharmacokinet 44:1135–1164.
   PubMed Web of Science ®Google Scholar
• Di Gion P, Kanefendt F, Lindauer A, et al. (2011). Clinical pharmacokinetics of tyrosine kinase inhibitors: Focus on pyrimidines, pyridines and pyrroles. Clin Pharmacokinet 50:551–603.
   PubMed Web of Science ®Google Scholar
• Dirven HA, Van Ommen B, Van Bladeren PJ. (1994). Involvement of human glutathione S-transferase isoenzymes in the conjugation of cyclophosphamide metabolites with glutathione. Cancer Res 54:6215–6220.
   PubMed Web of Science ®Google Scholar
• Dores-Sousa JL, Duarte JA, Seabra V, et al. (2015). The age factor for mitoxantrone's cardiotoxicity: Multiple doses render the adult mouse heart more susceptible to injury. Toxicology 329:106–119.
   PubMed Web of Science ®Google Scholar
• Dorr RT, Lagel K. (1994). Effect of sulfhydryl compounds and glutathione depletion on rat heart myocyte toxicity induced by 4-hydroperoxycyclophosphamide and acrolein in vitro. Chem Biol Interact 93:117–128.
   PubMed Web of Science ®Google Scholar
• Dumitriu E, Hulea V, Bilba N, et al. (1993). Synthesis of acrolein by vapor phase condensation of formaldehyde and acetaldehyde over oxides loaded zeolites. J Mol Catal 79:175–185.
   Web of Science ®Google Scholar
• Ehninger G, Proksch B, Hartmann F, et al. (1984). Mitoxantrone metabolism in the isolated perfused rat liver. Cancer Chemother Pharmacol 12:50–52.
   PubMed Web of Science ®Google Scholar
• Ehninger G, Schuler U, Proksch B, et al. (1990). Pharmacokinetics and metabolism of mitoxantrone: A review. Clin Pharmacokinet 18:365–380.
   PubMed Web of Science ®Google Scholar
• Ekhart C, Doodeman VD, Rodenhuis S, et al. (2008). Influence of polymorphisms of drug metabolizing enzymes (CYP2B6, CYP2C9, CYP2C19, CYP3A4, CYP3A5, GSTA1, GSTP1, ALDH1A1 and ALDH3A1) on the pharmacokinetics of cyclophosphamide and 4-hydroxycyclophosphamide. Pharmacogenet Genom 18:515–523.
   PubMed Web of Science ®Google Scholar
• Elsinghorst PW, Gütschow M. (2009). Synthesis of 2H- and 13C-labelled sunitinib and its primary metabolite. J Label Comp Radiopharm 52:360–365.
   Web of Science ®Google Scholar
• Escudier B, Eisen T, Stadler WM, et al. (2007). Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 356:125–134.
   PubMed Web of Science ®Google Scholar
• Faivre S, Delbaldo C, Vera K, et al. (2006). Safety, pharmacokinetic, and antitumor activity of SU11248, a novel oral multitarget tyrosine kinase inhibitor, in patients with cancer. J Clin Oncol 24:25–35.
   PubMed Web of Science ®Google Scholar
• Fenselau C, Kan MN, Rao SS, et al. (1977). Identification of aldophosphamide as a metabolite of cyclophosphamide in vitro and in vivo in humans. Cancer Res 37:2538–2543.
   PubMed Web of Science ®Google Scholar
• Fernández A, Sanguino A, Peng Z, et al. (2007). An anticancer C-Kit kinase inhibitor is reengineered to make it more active and less cardiotoxic. J Clin Invest 117:4044–4054.
   PubMed Web of Science ®Google Scholar
• Force T, Kolaja KL. (2011). Cardiotoxicity of kinase inhibitors: The prediction and translation of preclinical models to clinical outcomes. Nat Rev Drug Discov 10:111–126.
   PubMed Web of Science ®Google Scholar
• Force T, Krause DS, Van Etten RA. (2007). Molecular mechanisms of cardiotoxicity of tyrosine kinase inhibition. Nat Rev Cancer 7:332–344.
   PubMed Web of Science ®Google Scholar
• Frickhofen N, Beck FJ, Jung B, et al. (2002). Capecitabine can induce acute coronary syndrome similar to 5-fluorouracil. Ann Oncol 13:797–801.
   PubMed Web of Science ®Google Scholar
• Fujita K-I, Matsukawa A, Shibata K, et al. (1994). Synthesis of 5-fluorouridine 5′-diphosphate galactose from 5-fluorouridine by chemical phosphorylation and microbial uridylyl transfer. Carbohydr Res 265:299–302.
   PubMed Web of Science ®Google Scholar
• Fura A, Shu Y-Z, Zhu M, et al. (2004). Discovering drugs through biological transformation: Role of pharmacologically active metabolites in drug discovery. J Med Chem 47:4339–4351.
   PubMed Web of Science ®Google Scholar
• Gamcsik MP, Dolan ME, Andersson BS, Murray D. (1999). Mechanisms of resistance to the toxicity of cyclophosphamide. Curr Pharm Des 5:587–605.
   PubMed Web of Science ®Google Scholar
• Gardner ER, Burger H, Van Schaik RH, et al. (2006). Association of enzyme and transporter genotypes with the pharmacokinetics of imatinib. Clin Pharmacol Ther 80:192–201.
   PubMed Web of Science ®Google Scholar
• Gasser R, Funk C, Matzinger P, et al. (1999). Use of transgenic cell lines in mechanistic studies of drug metabolism. Toxicol In Vitro 13:625–632.
   PubMed Web of Science ®Google Scholar
• Ghassabian S, Rawling T, Zhou F, et al. (2012). Role of human CYP3A4 in the biotransformation of sorafenib to its major oxidized metabolites. Biochem Pharmacol 84:215–223.
   PubMed Web of Science ®Google Scholar
• Gibson GG, Skett P. (2001). Introduction to drug metabolism. 3rd ed. London: Nelson Thornes.
   Google Scholar
• Gieschke R, Burger HU, Reigner B, et al. (2003). Population pharmacokinetics and concentration–effect relationships of capecitabine metabolites in colorectal cancer patients. Br J Clin Pharmacol 55:252–263.
   PubMed Web of Science ®Google Scholar
• Goldman JM, Melo JV. (2003). Chronic myeloid leukemia—Advances in biology and new approaches to treatment. N Engl J Med 349:1451–1464.
   PubMed Web of Science ®Google Scholar
• Gross E, Busse B, Riemenschneider M, et al. (2008). Strong association of a common dihydropyrimidine dehydrogenase gene polymorphism with fluoropyrimidine-related toxicity in cancer patients. PLoS One 3:e4003.
   PubMed Web of Science ®Google Scholar
• Gschwind HP, Pfaar U, Waldmeier F, et al. (2005). Metabolism and disposition of imatinib mesylate in healthy volunteers. Drug Metab Dispos 33:1503–1512.
   PubMed Web of Science ®Google Scholar
• Gunaratna C. (2000). Drug metabolism and pharmacokinetics in drug discovery: A primer for bioanalytical chemists. Part I. Bioanal Sys Inc 19:17–23.
   Google Scholar
• Han H-K, Amidon GL. (2000). Targeted prodrug design to optimize drug delivery. AAPS PharmSci 2:48–58.
   Google Scholar
• Heggie GD, Sommadossi JP, Cross DS, et al. (1987). Clinical pharmacokinetics of 5-fluorouracil and its metabolites in plasma, urine, and bile. Cancer Res 47:2203–2206.
   PubMed Web of Science ®Google Scholar
• Heidelberger C. (1975). Fluorinated pyrimidines and their nucleosides. In: Sartorelli AC, Johns DG, eds. Antineoplastic and immunosuppressive agents: Part II. Berlin, Heidelberg: Springer Berlin Heidelberg, 193–231.
   Google Scholar
• Hill DL, Kirk MC, Struck RF. (1970). Isolation and identification of 4-ketocyclophosphamide, a possible active form of the antitumor agent cyclophosphamide. J Am Chem Soc 92:3207–3208.
   PubMed Web of Science ®Google Scholar
• Huang Q, Zhou C, Chen X, et al. (2015). Prodrug AST-003 improves the therapeutic index of the multi-targeted tyrosine kinase inhibitor sunitinib. PLoS One 10:e0141395.
   PubMed Web of Science ®Google Scholar
• Hudis CA. (2007). Trastuzumab—Mechanism of action and use in clinical practice. N Engl J Med 357:39–51.
   PubMed Web of Science ®Google Scholar
• Hudyma TW, Bush K, Colson KL, et al. (1993). Synthesis and release of doxorubicin from a cephalosporin based prodrug by a β-lactamase-immunoconjugate. Bioorg Med Chem Lett 3:323–328.
   Web of Science ®Google Scholar
• Huttunen KM, Raunio H, Rautio J. (2011). Prodrugs—From serendipity to rational design. Pharmacol Rev 63:750–771.
   PubMed Web of Science ®Google Scholar
• Ikenaka K, Shirasaka T, Kitano S, Fujii S. (1979). Effect of uracil on metabolism of 5-fluorouracil in vitro. Gan 70:353–359.
   PubMedGoogle Scholar
• U.S. Food and Drug Administration. (2005). Guidance for industry: Drug interaction studies – Study design, data analysis, and implications for dosing and labeling. FDA: Center for Drug Evaluation and Research.
   Google Scholar
• U.S. Food and Drug Administration. (2006). Guidance for industry: Safety testing of drug metabolites. FDA: Center for Drug Evaluation and Research.
   Google Scholar
• Jamieson D, Lee J, Cresti N, et al. (2014). Pharmacogenetics of adjuvant breast cancer treatment with cyclophosphamide, epirubicin and 5-fluorouracil. Cancer Chemother Pharmacol 74:667–674.
   PubMed Web of Science ®Google Scholar
• Jia L, Liu X. (2007). The conduct of drug metabolism studies considered good practice (II): In vitro experiments. Curr Drug Metab 8:822–829.
   PubMed Web of Science ®Google Scholar
• Joerger M, Huitema ADR, Meenhorst PL, et al. (2005). Pharmacokinetics of low-dose doxorubicin and metabolites in patients with AIDS-related kaposi sarcoma. Cancer Chemother Pharmacol 55:488–496.
   PubMed Web of Science ®Google Scholar
• Kerkelä R, Grazette L, Yacobi R, et al. (2006). Cardiotoxicity of the cancer therapeutic agent imatinib mesylate. Nat Med 12:908–916.
   PubMed Web of Science ®Google Scholar
• Khosravan R, Toh M, Garrett M, et al. (2010). Pharmacokinetics and safety of sunitinib malate in subjects with impaired renal function. J Clin Pharmacol 50:472–481.
   PubMed Web of Science ®Google Scholar
• Kil K-E, Ding Y-S, Lin K-S, et al. (2007). Synthesis and positron emission tomography studies of carbon-11-labeled imatinib (Gleevec). Nucl Med Biol 34:153–163.
   PubMed Web of Science ®Google Scholar
• Kratz F, Abu Ajaj K, Warnecke A. (2007). Anticancer carrier-linked prodrugs in clinical trials. Expert Opin Investig Drugs 16:1037–1058.
   PubMed Web of Science ®Google Scholar
• Kratz F, Warnecke A, Scheuermann K, et al. (2002). Probing the cysteine-34 position of endogenous serum albumin with thiol-binding doxorubicin derivatives. Improved efficacy of an acid-sensitive doxorubicin derivative with specific albumin-binding properties compared to that of the parent compound. J Med Chem 45:5523–5533.
   PubMed Web of Science ®Google Scholar
• Kratz F. (2007). DOXO-EMCH (INNO-206): The first albumin-binding prodrug of doxorubicin to enter clinical trials. Expert Opin Investig Drugs 16:855–866.
   PubMed Web of Science ®Google Scholar
• Lafrate AL, Katzenellenbogen JA. (2007). Improved chemical syntheses of 5,6-dihydro-5-fluorouracil. J Org Chem 72:8573–8576.
   PubMed Web of Science ®Google Scholar
• Lathia C, Lettieri J, Cihon F, et al. (2006). Lack of effect of ketoconazole-mediated CYP3A inhibition on sorafenib clinical pharmacokinetics. Cancer Chemother Pharmacol 57:685–692.
   PubMed Web of Science ®Google Scholar
• Lebrecht D, Geist A, Ketelsen UP, et al. (2007). The 6-maleimidocaproyl hydrazone derivative of doxorubicin (DOXO-EMCH) is superior to free doxorubicin with respect to cardiotoxicity and mitochondrial damage. Int J Cancer 120:927–934.
   PubMed Web of Science ®Google Scholar
• Lenihan DJ, Kowey PR. (2013). Overview and management of cardiac adverse events associated with tyrosine kinase inhibitors. Oncologist 18:900–908.
   PubMed Web of Science ®Google Scholar
• Levine ES, Friedman HS, Griffith OW, et al. (1993). Cardiac cell toxicity induced by 4-hydroperoxycyclophosphamide is modulated by glutathione. Cardiovasc Res 27:1248–1253.
   PubMed Web of Science ®Google Scholar
• Licata S, Saponiero A, Mordente A, Minotti G. (2000). Doxorubicin metabolism and toxicity in human myocardium: Role of cytoplasmic deglycosidation and carbonyl reduction. Chem Res Toxicol 13:414–420.
   PubMed Web of Science ®Google Scholar
• Lin JH, Lu AY. (1997). Role of pharmacokinetics and metabolism in drug discovery and development. Pharmacol Rev 49:403–449.
   PubMed Web of Science ®Google Scholar
• Lipshultz SE, Cochran TR, Franco VI, Miller TL. (2013). Treatment-related cardiotoxicity in survivors of childhood cancer. Nat Rev Clin Oncol 10:697–710.
   PubMed Web of Science ®Google Scholar
• Liu X, Jia L. (2007). The conduct of drug metabolism studies considered good practice (I): Analytical systems and in vivo studies. Curr Drug Metab 8:815–821.
   PubMed Web of Science ®Google Scholar
• Longley DB, Harkin DP, Johnston PG. (2003). 5-Fluorouracil: Mechanisms of action and clinical strategies. Nat Rev Cancer 3:330–338.
   PubMed Web of Science ®Google Scholar
• Low JE, Borch RF, Sladek NE. (1982). Conversion of 4-hydroperoxycyclophosphamide and 4-hydroxycyclophosphamide to phosphoramide mustard and acrolein mediated by bifunctional catalysis. Cancer Res 42:830–837.
   PubMed Web of Science ®Google Scholar
• Ludeman SM. (1999). The chemistry of the metabolites of cyclophosphamide. Curr Pharm Des 5:627–644.
   PubMed Web of Science ®Google Scholar
• Luffer-Atlas D. (2008). Unique/major human metabolites: Why, how, and when to test for safety in animals. Drug Metab Rev 40:447–463.
   PubMed Web of Science ®Google Scholar
• Ma S, Subramanian R, Xu Y, et al. (2008). Structural characterization of novel adenine dinucleotide phosphate conjugates of imatinib in incubations with rat and human liver microsomes. Drug Metab Dispos 36:2414–2418.
   PubMed Web of Science ®Google Scholar
• Ma S, Xu Y, Shou M. (2009). Characterization of imatinib metabolites in rat and human liver microsomes: Differentiation of hydroxylation from N-oxidation by liquid chromatography/atmospheric pressure chemical ionization mass spectrometry. Rapid Commun Mass Spectrom 23:1446–1450.
   PubMed Web of Science ®Google Scholar
• Maddin N, Husin A, Gan SH, et al. (2016). Impact of CYP3A4*18 and CYP3A5*3 polymorphisms on imatinib mesylate response among chronic myeloid leukemia patients in Malaysia. Oncol Ther 4:303–314.
   PubMed Web of Science ®Google Scholar
• Maharsy W, Aries A, Mansour O, et al. (2014). Ageing is a risk factor in imatinib mesylate cardiotoxicity. Eur J Heart Fail 16:367–376.
   PubMed Web of Science ®Google Scholar
• Maharsy W. (2015). Chemotherapy induced cardiotoxicity: Facts, breakthroughs, and challenges. J Med 5:51–56.
   Google Scholar
• Malet-Martino M, Martino R. (2002). Clinical studies of three oral prodrugs of 5-fluorouracil (capecitabine, UFT, S-1): A review. Oncologist 7:288–323.
   PubMed Web of Science ®Google Scholar
• Manley PW, Blasco F, Mestan J, Aichholz R. (2013). The kinetic deuterium isotope effect as applied to metabolic deactivation of imatinib to the des-methyl metabolite, CGP74588. Bioorg Med Chem 21:3231–3239.
   PubMed Web of Science ®Google Scholar
• Manthey CL, Sladek NE. (1988). Kinetic characterization of the catalysis of “activated” cyclophosphamide (4-hydroxycyclophosphamide/aldophosphamide) oxidation to carboxyphosphamide by mouse hepatic aldehyde dehydrogenases. Biochem Pharmacol 37:2781–2790.
   PubMed Web of Science ®Google Scholar
• Marull M, Rochat B. (2006). Fragmentation study of imatinib and characterization of new imatinib metabolites by liquid chromatography-triple-quadrupole and linear ion trap mass spectrometers. J Mass Spectrom 41:390–404.
   PubMed Web of Science ®Google Scholar
• Matsubara I, Kamiya J, Imai S. (1980). Cardiotoxic effects of 5-fluorouracil in the guinea pig. Jpn J Pharmacol 30:871–879.
   PubMedGoogle Scholar
• Mellor HR, Bell AR, Valentin JP, Roberts RR. (2011). Cardiotoxicity associated with targeting kinase pathways in cancer. Toxicol Sci 120:14–32.
   PubMed Web of Science ®Google Scholar
• Menna P, Gonzalez Paz O, Chello M, et al. (2012). Anthracycline cardiotoxicity. Expert Opin Drug Saf 11:S21–S36.
   PubMed Web of Science ®Google Scholar
• Mewes K, Blanz J, Ehninger G, et al. (1993). Cytochrome P-450-induced cytotoxicity of mitoxantrone by formation of electrophilic intermediates. Cancer Res 53:5135–5142.
   PubMed Web of Science ®Google Scholar
• Minotti G, Cavaliere AF, Mordente A, et al. (1995). Secondary alcohol metabolites mediate iron delocalization in cytosolic fractions of myocardial biopsies exposed to anticancer anthracyclines. Novel linkage between anthracycline metabolism and iron-induced cardiotoxicity. J Clin Invest 95:1595–1605.
   PubMed Web of Science ®Google Scholar
• Minotti G, Licata S, Saponiero A, et al. (2000). Anthracycline metabolism and toxicity in human myocardium: Comparisons between doxorubicin, epirubicin, and a novel disaccharide analogue with a reduced level of formation and [4Fe-4S] reactivity of its secondary alcohol metabolite. Chem Res Toxicol 13:1336–1341.
   PubMed Web of Science ®Google Scholar
• Mita MM, Natale RB, Wolin EM, et al. (2015). Pharmacokinetic study of aldoxorubicin in patients with solid tumors. Invest New Drugs 33:341–348.
   PubMed Web of Science ®Google Scholar
• Miwa M, Ura M, Nishida M, et al. (1998). Design of a novel oral fluoropyrimidine carbamate, capecitabine, which generates 5-fluorouracil selectively in tumours by enzymes concentrated in human liver and cancer tissue. Eur J Cancer 34:1274–1281.
   PubMed Web of Science ®Google Scholar
• Monneret C, Gagnet R, Florent J-C. (1993). Synthesis of cyclophosphamide analogs from aminotrideoxy sugars. Carbohydr Res 240:313–322.
   PubMed Web of Science ®Google Scholar
• Moore MJ. (1991). Clinical pharmacokinetics of cyclophosphamide. Clin Pharmacokinet 20:194–208.
   PubMed Web of Science ®Google Scholar
• Nakajima M, Komagata S, Fujiki Y, et al. (2007). Genetic polymorphisms of CYP2B6 affect the pharmacokinetics/pharmacodynamics of cyclophosphamide in Japanese cancer patients. Pharmacogenet Genomics 17:431–445.
   PubMed Web of Science ®Google Scholar
• Nakamura S, Aoki M, Mori A, et al. (2010). Analysis of cardiac toxicity caused by cyclophosphamide in the H9c2 cell line and isolated and perfused rat hearts. Gan Kagaku Ryoho 37:677–680.
   PubMedGoogle Scholar
• Nielsen DL, Andersson M, Kamby C. (2009). HER2-targeted therapy in breast cancer. Monoclonal antibodies and tyrosine kinase inhibitors. Cancer Treat Rev 35:121–136.
   PubMed Web of Science ®Google Scholar
• Nih. (2013). Capecitabine. Available from: https://www.cancer.gov/about-cancer/treatment/drugs/capecitabine [last accessed 22 Mar 2017].
   Google Scholar
• Obach RS. (2013). Pharmacologically active drug metabolites: Impact on drug discovery and pharmacotherapy. Pharmacol Rev 65:578–640.
   PubMed Web of Science ®Google Scholar
• Olson RD, Mushlin PS, Brenner DE, et al. (1988). Doxorubicin cardiotoxicity may be caused by its metabolite, doxorubicinol. Proc Natl Acad Sci USA 85:3585–3589.
   PubMed Web of Science ®Google Scholar
• Orphanos GS, Ioannidis GN, Ardavanis AG. (2009). Cardiotoxicity induced by tyrosine kinase inhibitors. Acta Oncol 48:964–970.
   PubMed Web of Science ®Google Scholar
• Panousis C, Kettle AJ, Phillips DR. (1997). Neutrophil-mediated activation of mitoxantrone to metabolites which form adducts with DNA. Cancer Lett 113:173–178.
   PubMed Web of Science ®Google Scholar
• Peer CJ, Sissung TM, Kim A, et al. (2012). Sorafenib is an inhibitor of UGT1A1 but is metabolized by UGT1A9: Implications of genetic variants on pharmacokinetics and hyperbilirubinemia. Clin Cancer Res 18:2099–2107.
   PubMed Web of Science ®Google Scholar
• Perez EA, Koehler M, Byrne J, et al. (2008). Cardiac safety of lapatinib: Pooled analysis of 3689 patients enrolled in clinical trials. Mayo Clin Proc 83:679–686.
   PubMed Web of Science ®Google Scholar
• Petros WP, Hopkins PJ, Spruill S, et al. (2005). Associations between drug metabolism genotype, chemotherapy pharmacokinetics, and overall survival in patients with breast cancer. J Clin Oncol 23:6117–6125.
   PubMed Web of Science ®Google Scholar
• Pleiss U, Gerisch M, Seidel D. (2006). Syntheses of [2H3, 15N], [14C]Nexavar™ and its labeled metabolites. J Label Comp Radiopharm 49:603–613.
   Web of Science ®Google Scholar
• Pratt CB, Vietti TJ, Etcubanas E, et al. (1986). Novantrone for childhood malignant solid tumors. A pediatric oncology group phase II study. Invest New Drugs 4:43–48.
   PubMed Web of Science ®Google Scholar
• Raj S, Franco VI, Lipshultz SE. (2014). Anthracycline-induced cardiotoxicity: A review of pathophysiology, diagnosis, and treatment. Curr Treat Options Cardiovasc Med 16:315.
   PubMedGoogle Scholar
• Rautio J, Kumpulainen H, Heimbach T, et al. (2008). Prodrugs: Design and clinical applications. Nat Rev Drug Discov 7:255–270.
   PubMed Web of Science ®Google Scholar
• Reis-Mendes A, Gomes AS, Carvalho RA, et al. (2017). Naphthoquinoxaline metabolite of mitoxantrone is less cardiotoxic than the parent compound and it can be a more cardiosafe drug in anticancer therapy. Arch Toxicol 91:1871–1890.
   PubMed Web of Science ®Google Scholar
• Reis-Mendes AF, Sousa E, De Lourdes Bastos M, Costa VM. (2016). The role of the metabolism of anticancer drugs in their induced-cardiotoxicity. Curr Drug Metab 17:75–90.
   Web of Science ®Google Scholar
• Ren S, Yang JS, Kalhorn TF, Slattery JT. (1997). Oxidation of cyclophosphamide to 4-hydroxycyclophosphamide and deschloroethylcyclophosphamide in human liver microsomes. Cancer Res 57:4229–4235.
   PubMed Web of Science ®Google Scholar
• Reszka K, Kolodziejczyk P, William Lown J. (1986). Horseradish peroxidase-catalyzed oxidation of mitoxantrone: Spectrophotometric and electron paramagnetic resonance studies. J Free Radic Biol Med 2:25–32.
   PubMedGoogle Scholar
• Richard B, Fabre G, De Sousa G, et al. (1991). Interspecies variability in mitoxantrone metabolism using primary cultures of hepatocytes isolated from rat, rabbit and humans. Biochem Pharmacol 41:255–262.
   PubMed Web of Science ®Google Scholar
• Rochat B. (2005). Role of cytochrome P450 activity in the fate of anticancer agents and in drug resistance: Focus on tamoxifen, paclitaxel and imatinib metabolism. Clin Pharmacokinet 44:349–366.
   PubMed Web of Science ®Google Scholar
• Rollas S, Küçükgüzel ŞG. (2008). Hydrazone, amide, carbamate, macromolecular and other prodrugs of doxorubicin. Open Drug Deliv J 2:77–85.
   Google Scholar
• Rooseboom M, Commandeur JNM, Vermeulen NPE. (2004). Enzyme-catalyzed activation of anticancer prodrugs. Pharmacol Rev 56:53–102.
   PubMed Web of Science ®Google Scholar
• Rossato LG, Costa VM, Dallegrave E, et al. (2014). Mitochondrial cumulative damage induced by mitoxantrone: Late onset cardiac energetic impairment. Cardiovasc Toxicol 14:30–40.
   PubMed Web of Science ®Google Scholar
• Rossato LG, Costa VM, De Pinho PG, et al. (2013). The metabolic profile of mitoxantrone and its relation with mitoxantrone-induced cardiotoxicity. Arch Toxicol 87:1809–1820.
   PubMed Web of Science ®Google Scholar
• Salvatorelli E, Menna P, Minotti G. (2015). Managing anthracycline-induced cardiotoxicity: Beginning with the end in mind. Future Cardiol 11:363–366.
   PubMedGoogle Scholar
• Sawyer DB. (2013). Anthracyclines and heart failure. N Engl J Med 368:1154–1156.
   PubMed Web of Science ®Google Scholar
• Senturk T, Kanat O, Evrensel T, Aydinlar A. (2009). Capecitabine-induced cardiotoxicity mimicking myocardial infarction. Neth Heart J 17:277–280.
   PubMed Web of Science ®Google Scholar
• Seong SJ, Lim M, Sohn SK, et al. (2013). Influence of enzyme and transporter polymorphisms on trough imatinib concentration and clinical response in chronic myeloid leukemia patients. Ann Oncol 24:756–760.
   PubMed Web of Science ®Google Scholar
• Sharma A, Burridge PW, Mckeithan WL, et al. (2017). High-throughput screening of tyrosine kinase inhibitor cardiotoxicity with human induced pluripotent stem cells. Sci Transl Med 9:eaaf2584.
   PubMed Web of Science ®Google Scholar
• Shaw IC, Graham MI, Mclean AEM. (1983). 2-Chloroacetaldehyde, a metabolite of cyclophosphamide in the rat. Xenobiotica 13:433–437.
   PubMed Web of Science ®Google Scholar
• Shipp NG, Dorr RT, Alberts DS, et al. (1993). Characterization of experimental mitoxantrone cardiotoxicity and its partial inhibition by ICRF-187 in cultured neonatal rat heart cells. Cancer Res 53:550–556.
   PubMed Web of Science ®Google Scholar
• Skarka A, Skarydova L, Stambergova H, Wsol V. (2011). Anthracyclines and their metabolism in human liver microsomes and the participation of the new microsomal carbonyl reductase. Chem Biol Interact 191:66–74.
   PubMed Web of Science ®Google Scholar
• Slamon DJ, Leyland-Jones B, Shak S, et al. (2001). Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344:783–792.
   PubMed Web of Science ®Google Scholar
• Smith LA, Cornelius VR, Plummer CJ, et al. (2010). Cardiotoxicity of anthracycline agents for the treatment of cancer: Systematic review and meta-analysis of randomised controlled trials. BMC Cancer 10:337.
   PubMed Web of Science ®Google Scholar
• Speed B, Bu HZ, Pool WF, et al. (2012). Pharmacokinetics, distribution, and metabolism of [14C]sunitinib in rats, monkeys, and humans. Drug Metab Dispos 40:539–555.
   PubMed Web of Science ®Google Scholar
• Speed W, Bello C, Peng G, et al. (2008). In vitro and in vivo metabolism of sunitinib in nonclinical species and humans. Cancer Res 68:1285–1285.
   Google Scholar
• Stella VJ, Charman WNA, Naringrekar VH. (1985). Prodrugs. Do they have advantages in clinical practice? Drugs 29:455–473.
   PubMed Web of Science ®Google Scholar
• Struck RF, Schmid SM, Waud WR. (1994). Antitumor activity of halogen analogs of phosphoramide, isophosphoramide, and triphosphoramide mustards, the cytotoxic metabolites of cyclophosphamide, ifosfamide, and trofosfamide. Cancer Chemother Pharmacol 34:191–196.
   PubMed Web of Science ®Google Scholar
• Struck RF, Thorpe MC, Coburn WC, Laster WR. (1974). Cyclophosphamide. Complete inhibition of murine leukemia L1210 in vivo by a Fenton oxidation product. J Am Chem Soc 96:313–315.
   PubMed Web of Science ®Google Scholar
• Strumberg D, Clark JW, Awada A, et al. (2007). Safety, pharmacokinetics, and preliminary antitumor activity of sorafenib: A review of four phase I trials in patients with advanced refractory solid tumors. Oncologist 12:426–437.
   PubMed Web of Science ®Google Scholar
• Takanashi S, Bachur NR. (1976). Adriamycin metabolism in man. Evidence from urinary metabolites. Drug Metab Dispos 4:79–87.
   PubMed Web of Science ®Google Scholar
• Telli ML, Witteles RM, Fisher GA, Srinivas S. (2008). Cardiotoxicity associated with the cancer therapeutic agent sunitinib malate. Ann Oncol 19:1613–1618.
   PubMed Web of Science ®Google Scholar
• Unger C, Haring B, Medinger M, et al. (2007). Phase I and pharmacokinetic study of the (6-maleimidocaproyl)hydrazone derivative of doxorubicin. Clin Cancer Res 13:4858–4866.
   PubMed Web of Science ®Google Scholar
• Van Erp NP, Gelderblom H, Guchelaar HJ. (2009). Clinical pharmacokinetics of tyrosine kinase inhibitors. Cancer Treat Rev 35:692–706.
   PubMed Web of Science ®Google Scholar
• Van Erp NP, Gelderblom H, Karlsson MO, et al. (2007). Influence of CYP3A4 inhibition on the steady-state pharmacokinetics of imatinib. Clin Cancer Res 13:7394–7400.
   PubMed Web of Science ®Google Scholar
• Veal GJ, Cole M, Chinnaswamy G, et al. (2016). Cyclophosphamide pharmacokinetics and pharmacogenetics in children with B-cell non-Hodgkin's lymphoma. Eur J Cancer 55:56–64.
   PubMed Web of Science ®Google Scholar
• Vejpongsa P, Yeh ETH. (2014). Prevention of anthracycline-induced cardiotoxicity: Challenges and opportunities. J Am Coll Cardiol 64:938–945.
   PubMed Web of Science ®Google Scholar
• Venn RF. (2008). Principles and practice of bioanalysis. 2nd ed. Boca Raton (FL): CRC Press.
   Google Scholar
• Voon PJ, Yap HL, Ma CYT, et al. (2013). Correlation of aldo‐ketoreductase (AKR) 1C3 genetic variant with doxorubicin pharmacodynamics in Asian breast cancer patients. Br J Clin Pharmacol 75:1497–1505.
   PubMed Web of Science ®Google Scholar
• Walko CM, Lindley C. (2005). Capecitabine: A review. Clin Ther 27:23–44.
   PubMed Web of Science ®Google Scholar
• Weenen H, Van Maanen JMS, De Planque MM, et al. (1984). Metabolism of 4′-modified analogs of doxorubicin. Unique glucuronidation pathway for 4′-epidoxorubicin. Eur J Cancer Clin Oncol 20:919–926.
   PubMedGoogle Scholar
• Wijesinghe N, Thompson PI, McAlister H. (2006). Acute coronary syndrome induced by capecitabine therapy. Heart Lung Circ 15:337–339.
   PubMedGoogle Scholar
• Wolf CR, Macpherson JS, Smyth JF. (1986). Evidence for the metabolism of mitozantrone by microsomal glutathione transferases and 3-methylcholanthrene-inducible glucuronosyl transferases. Biochem Pharmacol 35:1577–1581.
   PubMed Web of Science ®Google Scholar
• Yule SM, Price L, McMahon AD, et al. (2004). Cyclophosphamide metabolism in children with non-Hodgkin's lymphoma. Clin Cancer Res 10:455.
   PubMed Web of Science ®Google Scholar
• Zhang RW, Soong SJ, Liu TP, et al. (1992). Pharmacokinetics and tissue distribution of 2-fluoro-beta-alanine in rats. Potential relevance to toxicity pattern of 5-fluorouracil. Drug Metab Dispos 20:113–119.
   PubMed Web of Science ®Google Scholar
• Zhang S, Liu X, Bawa-Khalfe T, et al. (2012). Identification of the molecular basis of doxorubicin-induced cardiotoxicity. Nat Med 18:1639–1642.
   PubMed Web of Science ®Google Scholar