Introduction: Capecitabine (CAP) is an oral antineoplastic pro-drug, whose initial step of activation is carboxylesterase (CES) dependent. The main conversion of CAP to 5-DFCR occurs in the liver by CES1 and a minor part - in the gastrointestinal tract (GIT) by CES2. Usually, the enteral pro-drug activation is associated with the appearance of fluoropyrimidine GIT toxicity, which may be dose-limiting and life-threatening for the patient. Thus, it is important to clear out the factors that could influence on the activity of both CES isozymes.
Aim: The aim of the present study was to present the mechanism of hydrolysis, sources of variability and modulation possibilities of CESs, that could affect the treatment with CAP.
Materials and Methods: A systematic review of the scientific databases in PubMed, Science Direct and Google Scholar was conducted.
Results: The literature data showed up to 89% inter-individual variability in the plasma content of CAP and its metabolites. It was also established that factors, such as genetic polymorphisms, age, gender, and diseases, are responsible for these variabilities. Enzyme inhibitors and inductors, on the other hand, are among the factors that could be controlled and used as reliable modulators for CAP therapy. In fact, some authors found that the inhibition of CAP hydrolysis at CES2 level could reduce the common GIT toxicity and improve the bioavailability of the pro-drug.
Conclusion: In accordance with the individual patient, the CES activity modulation approach could be used for the enhancement of the CAP therapeutic index. However, further detailed in vivo researches are needed to achieve categorical and applicable results.
Walko CM, Lindley C. Capecitabine: A review. Clin Ther. 2005;27(1):23-44. doi: 10.1016/j.clinthera.2005.01.005.
Ishitsuka H. Capecitabine: preclinical pharmacology studies. Invest New Drugs. 2000;18(4):343-54. doi: 10.1023/a:1006497231579.
Miwa M, Ura M, Nishida M, Sawada N, Ishikawa T, Mori K, et al. 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. 1998;34(8):1274 – 81. doi: 10.1016/S0959-8049(98)00058-6.
Schüller J, Cassidy J, Dumont E, Roos B, Durston S, Banken L, et al. Preferential activation of capecitabine in tumor following oral administration to colorectal cancer patients. Cancer Chemother Pharmacol. 2000;45(4):291–7. doi: 10.1007/s002800050043.
Ribelles N, Lopez-Siles J, Sanchez A, Gonzalez E, Sanchez MJ, Carabantes F, et al. A carboxylesterase 2 gene polymorphism as predictor of capecitabine on response and time to progression. Curr Drug Metab, 2008;9(4):336 – 43. doi: 10.2174/138920008784220646.
Fukami T, Yokoi T. The emerging role of human esterases. Drug Metab Pharmacokinet. 2012;27(5):466-77. doi: 10.2133/dmpk.DMPK-12-RV-042.
IUBMB Enzyme Nomenclature [Internet]. London: Nomenclature Committee of the International Union of Biochemistry and Molecular Biology (NC-IUBMB); [updated 2020 Febr 17; cited 2020 Apr 9]. Recommendations on Biochemical & Organic Nomenclature, Symbols & Terminology etc. Available from: https://www.qmul.ac.uk/sbcs/iubmb/enzyme/EC3/1/1/1.html
Hosokawa M. Structure and catalytic properties of carboxylesterase isozymes involved in metabolic activation of prodrugs. Molecules. 2008;13(2):412-31. doi: 10.3390/molecules13020412.
Aldridge WN. The esterases: perspectives and problems. Chem Biol Interact. 1993;87(1-3):5-13. doi: 10.1016/0009-2797(93)90019-u.
Hatfield MJ, Tsurkan L, Garrett M, Shaver T, Edwards CC, Hyatt JL, et al. Organ-specific carboxylesterase profiling identifies the small intestine and kidney as major contributors of activation of the anticancer prodrug CPT-11. Biochem Pharmacol. 2011;81(1):24-31. doi: 10.1016/j.bcp.2010.09.001.
Ross MK, Crow JA. Human carboxylesterases and their role in xenobiotic and endobiotic metabolism. J Biochem Mol Toxicol. 2007;21(4):187-96. doi: 10.1002/jbt.20178.
Di L. The impact of carboxylesterases in drug metabolism and pharmacokinetics. Curr Drug Metab. 2019;20(2):91-102. doi: 10.2174/1389200219666180821094502.
Satoh T, Hosokawa M. Carboxylesterases: structure, function and polymorphism in mammals. J Pestic Sci. 2010;35(3):218-28. doi: 10.1584/jpestics.
Williams ET, Wang H, Wrighton SA, Qian YW, Perkins EJ. Genomic analysis of the carboxylesterases: Identification and classification of novel forms. Mol Phylogenet Evol. 2010;57(1):23-34. doi: 10.1016/j.ympev.2010.05.018.
Wang D, Zou L, Jin Q, Hou J, Ge G, Yang L. Human carboxylesterases: a comprehensive review. Acta Pharm Sin B. 2018;8(5):699-712. doi: 10.1016/j.apsb.2018.05.005.
Hatfield MJ, Umans RA, Hyatt JL, Edwards CC, Wierdl M, Tsurkan L. Carboxylesterases: General detoxifying enzymes. Chem Biol Interact. 2016;259(B):327-31. doi: 10.1016/j.cbi.2016.02.011.
Chen F, Zhang B, Parker RB, Laizure SC. Clinical implications of genetic variation in carboxylesterase drug metabolism. Expert Opin Drug Metab Toxicol. 2018;14(2):131-42. doi: 10.1080/17425255.2018.1420164.
Vistoli G, Pedretti A, Mazzolari A, Bolchi C, Testa B. Influence of ionization state on the activation of temocapril by hCES1: a molecular-dynamics study. Chem Biodivers. 2009;6(11):2092–100. doi: 10.1002/cbdv.200900174.
Vistoli G, Pedretti A, Mazzolari A, Testa B. Homology modeling and metabolism prediction of human carboxylesterase-2 using docking analyses by GriDock: a parallelized tool based on AutoDock 4.0. J Comput Aided Mol. 2010;24(9):771-87. doi: 10.1007/s10822-010-9373-1.
Shimma N, Umeda I, Arasaki M, Murasaki C, Masubuchi K, Kohchi Y, et al. The design and synthesis of a new tumor-selective fluoropyrimidine carbamate, capecitabine. Bioorg Med Chem. 2000;8(7):1697-706. doi: 10.1016/s0968-0896(00)00087-0.
Imai T. Human carboxylesterase isozymes: catalytic properties and rational drug design. Drug Metab Pharmacokinet. 2006;21(3):173–85. doi: 10.2133/dmpk.21.173.
Maggo G, Grover SC, Grin A. Capecitabine induced colitis. Pathol Res Pract. 2014;210(9):606-8. doi: 10.1016/j.prp.2014.05.005.
Stathopoulos GP, Koutantos J, Lazaki H, Rigatos SK, Stathopoulos J, Deliconstantinos G. Capecitabine (Xeloda) as monotherapy in advanced breast and colorectal cancer: effectiveness and side-effects. Anticancer Res. 2007;27(3B):1653-6. PMID: 17595791.
Reigner B, Watanabe T, Schuller J, Lucraft H, Sasaki Y, Bridgewater J. Pharmacokinetics of capecitabine (Xeloda) in Japanese and Caucasian patients with breast cancer. Cancer Chemother Pharmacol. 2003;52(3):193-201. doi: 10.1007/s00280-003-0642-8.
Marsé H, Van Cutsem E, Grothey A, Valverde S. Management of adverse events and other practical considerations in patients receiving capecitabine (Xeloda®). Eur J Oncol Nurs. 2004;8(1):16-30. doi: 10.1016/j.ejon.2004.06.006.
Wagstaff AJ, Ibbotson T, Goa KL. Capecitabine: a review of its pharmacology and therapeutic efficacy in the management of advanced breast cancer. Drugs. 2003;63(2):217-36. doi: 10.2165/00003495-200363020-00009.
Mercier C, Ciccolini J. Profiling dihydropyrimidine dehydrogenase deficiency in patients with cancer undergoing 5-fluorouracil/capecitabine therapy. Clin Colorectal Cancer. 2006;6(4)288-96. doi: 10.3816/CCC.2006.n.047.
Tabata T, Katoh M, Tokudome S, Nakajima M, Yokoi T. Identification of the cytosolic carboxylesterase catalyzing the 5′-deoxy-5-fluorocytidine formation from capecitabine in human liver. Drug Metab Dispos. 2004;32(10):1103-10. doi: 10.1124/dmd.104.000554.
Hamzic S, Kummer D, Milesi S, Mueller D, Joerger M, Aebi S. Novel genetic variants in carboxylesterase 1 predict severe early‐onset capecitabine‐related toxicity. Clin Pharmacol Ther. 2017;102(5):796-804. doi: 10.1002/cpt.641.
Sato Y, Miyashita A, Iwatsubo T, Usui T. Simultaneous absolute protein quantification of carboxylesterases 1 and 2 in human liver tissue fractions using liquid chromatography-tandem mass spectrometry. Drug Metab Dispos. 2012;40(7):1389-96. doi: 10.1124/dmd.112.045054.
Hines RN, Simpson PM, McCarver DG. Age-dependent human hepatic carboxylesterase 1 (CES1) and carboxylesterase 2 (CES2) postnatal ontogeny. Drug Metab Dispos. 2016;44(7):959-66. doi: 10.1124/dmd.115.068957.
Vesell ES. Advances in pharmacogenetics and pharmacogenomics. Clin Pharmacol. 2000;40(9):930-8. doi: 10.1016/j.bcp.2008.10.005.
Langmann T, Becker A, Aslanidis C, Notka F, Ullrich H, Schwer H, et al. Structural organization and characterization of the promoter region of a human carboxylesterase gene. Biochim Biophys Acta. 1997;1350(1):65-74. doi: 10.1016/S0167-4781(96)00142-X.
Hamzic S, Kummer D, Milesi S, Mueller D, Joerger M, Aebi S, et al. Novel genetic variants in carboxylesterase 1 predict severe early-onset capecitabine-related toxicity. Clin Pharmacol Ther. 2017;102(5):796-804. doi: 10.1002/cpt.641.
Yang D, Pearce RE, Wang X, Gaedigk R, Wan YJ, Yan B. Human carboxylesterases HCE1 and HCE2: Ontogenic expression, inter-individual variability and differential hydrolysis of oseltamivir, aspirin, deltamethrin and permethrin. Biochem Pharmacol. 2009;77(2):238-47. doi: 10.1016/j.bcp.2008.10.005.
Zhu HJ, Appel DI, Jiang Y, Markowitz JS. Age- and Sex-related expression and activity of carboxylesterase 1 and 2 in mouse and human liver. Drug Metab Dispos. 2009;37(9):1819-25. doi: 10.1124/dmd.109.028209.
Cassidy J, Twelves C, Cameron D, Steward W, O'Byrne K, Jodrell D, et al. Bioequivalence of two tablet formulations of capecitabine and exploration of age, gender, body surface area, and creatinine clearance as factors influencing systemic exposure in cancer patients. Cancer Chemother Pharmacol. 1999;44(6):453-60. doi: 10.1007/s002800051118.
McGavin JK, Goa KL. Capecitabine. drugs. 2001;61(15):2309–26. doi: 10.2165/00003495-200161150-00015.
Yang J, Shi D, Yang D, Song X, Yan B. Interleukin-6 alters the cellular responsiveness to clopidogrel, irinotecan, and oseltamivir by suppressing the expression of carboxylesterases HCE1 and HCE2. Mol Pharmacol. 2007;72(3):686-94. doi: 10.1124/mol.107.036889.
Unver N, McAllister F. IL-6 family cytokines: Key inflammatory mediators as biomarkers and potential therapeutic targets. CYTOKINE GROWTH F R. 2018;41:10-7. doi: 10.1016/j.cytogfr.2018.04.004.
Eriksson A, Gretzer C, Wallerstedt S. Elevation of cytokines in peritoneal fluid and blood in patients with liver cirrhosis. Hepato-gastroenterology, 2004;51(56):505-9. PMID: 15086192.
Thiollet M, Funck-Brentano C, Grange J, Midavaine M, Resplandy G, Jaillon P. The pharmacokinetics of perindopril in patients with liver cirrhosis. Br J Clin Pharmacol. 1992;33(3):326-8. doi: 10.1111/j.1365-2125.1992.tb04045.x.
Valle A, Catalán V, Rodríguez A, Rotellar F, Valentí V, Silva C, et al. Identification of liver proteins altered by type 2 diabetes mellitus in obese subjects. Liver Int. 2012;32(6):951-61. doi: 10.1111/j.1478-3231.2012.02765.x.
Jensen SA, Sørensen JB. Risk factors and prevention of cardiotoxicity induced by 5-fluorouracil or capecitabine. Cancer Chemother Pharmacol. 2006;58(4):487–93. doi: 10.1007/s00280-005-0178-1.
Laizure SC, Herring V, Hu Z, Witbrodt K, Parker RB. The role of human carboxylesterases in drug metabolism. Pharmacotherapy. 2013;33(2):210-22. doi: 10.1002/phar.1194.
Beroza P, Damodaran K, Lum RT. Target-related affinity profiling: Telik's lead discovery technology. Curr Top Med Chem. 2005; 5(4):371–81. doi: 10.2174/1568026053828394.
Hatfield MJ, Potter PM. Carboxylesterase inhibitors. Expert Opin Ther Pat. 2011;21(8):1159–71. doi: 10.1517/13543776.2011.586339.
Hyatt JL, Moak T, Hatfield MJ, Tsurkan L, Edwards CC, Wierdl M, et al. Selective inhibition of carboxylesterases by isatins, indole-2,3-diones. J Med Chem. 2007;50(8):1876-85. doi: 10.1021/jm061471k.
Parkinson EI, Hatfield MJ, Tsurkan L, Hyatt JL, Edwards CC, Hicks LD, et al. Requirements for mammalian carboxylesterase inhibition by substituted ethane-1,2-diones. Bioorgan Med Chem. 2011;19(15):4635-43. doi: 10.1016/j.bmc.2011.06.012.
Wadkins RM, Hyatt JL, Wei X, Yoon KJP, Wierdl M, Edwards CC, et al. Identification and characterization of novel benzil (diphenylethane-1,2-dione) analogues as inhibitors of mammalian carboxylesterases. J Med Chem. 2005;48(8):2906-15. doi: 10.1021/jm049011j.
Zou LW, Jin Q, Wang DD, Qian QK, Hao DC, Ge GB, et al. Carboxylesterase inhibitors: An update. Curr Med Chem. 2018;25(14):1627-49. doi: 10.2174/0929867325666171204155558.
Fleming CD, Bencharit S, Edwards CC, Hyatt JL, Tsurkan L, Bai F, et al. Structural insights into drug processing by human carboxylesterase 1: Tamoxifen, mevastatin, and inhibition by benzil. J Mol Biol. 2005;352(1):165-77. doi: 10.1016/j.jmb.2005.07.016.
Hyatt JL, Stacy V, Wadkins RM, Yoon KJ, Wierdl M, Edwards CC, et al. Inhibition of carboxylesterases by benzil (diphenylethane-1,2-dione) and heterocyclic analogues is dependent upon the aromaticity of the ring and the flexibility of the dione moiety. J Med Chem. 2005;48(17):5543-50. doi: 10.1021/jm0504196.
Hyatt JL, Tsurkan L, Wierdl M, Edwards CC, Danks MK, Potter PM. Intracellular inhibition of carboxylesterases by benzil: modulation of CPT-11 cytotoxicity. Mol Cancer Ther. 2006;5(9):2281-8. doi: 10.1158/1535-7163.MCT-06-0160.
Hatfield MJ, Binder RJ, Gannon R, Fratt EM, Bowling J, Potter PM, Potent, irreversible inhibition of human carboxylesterases by tanshinone anhydrides isolated from Salvia miltiorrhiza (“Danshen”). J Nat Prod. 2018;81(11):2410-8. doi: 10.1021/acs.jnatprod.8b00378.
Wadkins RM, Hyatt JL, Yoon KJP, Morton CL, Lee RE, Damodaran K, et al. Discovery of novel selective inhibitors of human intestinal carboxylesterase for the amelioration of irinotecan-induced diarrhea: synthesis, quantitative structure-activity relationship analysis, and biological activity. Mol Pharmacol. 2004;65(6)1336-43. doi: 10.1124/mol.65.6.1336.
Hicks LD, Hyatt JL, Stoddard S, Tsurkan L, Edwards CC, Wadkins RM, et al. Improved, selective, human intestinal carboxylesterase inhibitors designed to modulate 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (Irinotecan; CPT-11) toxicity. J Med Chem. 2009;52(12):3742– 52. doi: 10.1021/jm9001296.
Wu MH, Chen PX, Remo BF, Cook EH, Das S, Dolan ME. Characterization of multiple promoters in the human carboxylesterase 2 gene. Pharmacogenetics. 2003;13(7):425-35. doi: 10.1097/00008571-200307000-00008.
Lamego J, Cunha B, Peixoto C, Sousa MF, Alves PM, Simplicio AL, et al. Carboxylesterase 2 production and characterization in human cells: new insights into enzyme oligomerization and activity. Appl Microbiol Biotechnol. 201397(3):1161-73. doi: 10.1007/s00253-012-3994-3.
Wheelock CE, Severson TF, Hammock BD. Synthesis of new carboxylesterase inhibitors and evaluation of potency and water solubility. Chem Res Toxicol. 2001;14(12):1563-72. doi: 10.1021/tx015508+.
Wadkins RM, Hyatt JL, Edwards CC, Tsurkan L, Redinbo MR, Wheelock CE, et al. Analysis of mammalian carboxylesterase inhibition by trifluoromethylketone-containing compounds. Mol Pharmacol. 2007;71(3):713-23. doi: 10.1124/mol.105.021683.
Ojima I, Jameison FA, Pete B, Radunz H, Schittenhelm C, Lindner HJ, et al. Design, synthesis and enzyme inhibitory activities of new trifluoromethyl containing inhibitors for angiotensin converting enzyme. Drug design and discovery. 1994;11(2):91-113. PMID: 8075303.
Buchheit D, Dragan CA, Schmitt EI, Bureik M. Production of ibuprofen acyl glucosides by human UGT2B7. Drug Metab Dispos. 2011;39(12):2174-81. doi: 10.1124/dmd.111.041640.
Di Meo F, Steel M, Nicolas P, Marquet P, Duroux JL, Trouillas P. Acylglucuronide in alkaline conditions: migration vs. hydrolysis. J Mol Model. 2013;19(6):2423-32. doi: 10.1007/s00894-013-1790-3.
Inoue NR, Hall A, Lai WG, Williams ET. Reversible Inhibition of Human Carboxylesterases by Acyl Glucuronides. Drug Metab Dispos. 2013;41(4):698-703. doi: 10.1124/dmd.112.050252.
Zou LW, Dou TY, Wang P, Lei W, Weng ZM, Hou J, et al. Structure-activity relationships of pentacyclic triterpenoids as potent and selective inhibitors against human carboxylesterase 1. Front Pharmacol. 2017;8:438. doi: 10.3389/fphar.2017.00435.
Zou LW, Li YG, Wang P, Zhou K, Hou J, Jin Q, et al. Design, synthesis, and structure-activity relationship study of glycyrrhetinic acid derivatives as potent and selective inhibitors against human carboxylesterase 2. Eur J Med Chem. 2016;112:280-8. doi: 10.1016/j.ejmech.2016.02.020.
Li YG, Hou J, Li SY, Lv X, Ning J, Wang P, et al. Fructus psoraleae contains natural compounds with potent inhibitory effects towards human carboxylesterase 2. Fitoterapia. 2015;101:99-106. doi: 10.1016/j.fitote.2015.01.004.
Sun DX, Ge GB, Dong PP, Cao YF, Fu Z W, Ran RX, et al. Inhibition behavior of fructus psoraleae's ingredients towards human carboxylesterase 1 (hCES1). Xenobiotica. 2016;46(6)503-10. doi: 10.3109/00498254.2015.1091521.
Liu YJ, Li SY, Hou J, Liu YF, Wang DD, Jiang YS, et al. Identification and characterization of naturally occurring inhibitors against human carboxylesterase 2 in White Mulberry Root-bark. Fitoterapia. 2016;115:57-63. doi: 10.1016/j.fitote.2016.09.022.
Crow JA, Herring KL, Xie S, Borazjani A, Potter PM, Ross MK. Inhibition of carboxylesterase activity of THP1 monocytes/ macrophages and recombinant human carboxylesterase 1 by oxysterols and fatty acids. Biochim Biophys Acta. 2010;1801(1):31-41. doi: 10.1016/j.bbalip.2009.09.002.
Xu J, Qiu JC, Ji X, Guo HL, Wang X, Zhang B, et al. Potential pharmacokinetic herb-drug interactions: have we overlooked the importance of human carboxylesterases 1 and 2? Curr Drug Metab. 2019;20(2):130-7. doi: 10.2174/1389200219666180330124050.
Fukami T, Takahashi S, Nakagawa N, Maruichi T, Nakajima M, Yokoi T. In vitro evaluation of inhibitory effects of antidiabetic and antihyperlipidemic drugs on human carboxylesterase activities. Drug Metab Dispos. 2010;38(12):2173-8. doi: 10.1124/dmd.110.034454.
Yanjiao X, Chengliang Z, Xiping L, Tao W, Xiuhua R, Dong, L. Evaluation of the inhibitory effects of antihypertensive drugs on human carboxylesterase in vitro. Drug Metab Pharmacokinet. 2013;28(6):468-74. doi: 10.2133/dmpk.dmpk-12-rg-143.
Umehara KI, Zollinger M, Kigondu E, Witschi M, Juif C, Huth F, et al. Esterase phenotyping in human liver in vitro: specificity of carboxylesterase inhibitors. Xenobiotica. 2016;46(10):862-7. doi: 10.3109/00498254.2015.1133867.
Quinney SK, Sanghani SP, Davis WI, Hurley TD, Sun Z, Murry DJ, et al. Hydrolysis of capecitabine to 5′-deoxy-5-fluorocytidine by human carboxylesterases and inhibition by loperamide. J. Pharmacol. Exp. Ther. 2005;313(3):1011-6. doi: 10.1124/jpet.104.081265.
Zhang C, Xu Y, Zhong Q, Li X, Gao P, Feng C, et al. In vitro evaluation of the inhibitory potential of pharmaceutical excipients on human carboxylesterase 1A and 2. PLoS ONE. 2014;9(4):e93819. doi: 10.1371/journal.pone.0093819.
Casida JE, Durkin KA. Anticholinesterase insecticide retrospective. Chem Biol Interact. 2013;203(1):221-5. doi: 10.1016/j.cbi.2012.08.002.
Tsurkan LG, Hatfield MJ, Edwards CC, Hyatt JL, Potter PM. Inhibition of human carboxylesterases hCE1 and hiCE by cholinesterase inhibitors. Chem Biol Interact. 2013;203(1):226-30. doi: 10.1016/j.cbi.2012.10.018.
Casida JE, Quistad GB. Serine hydrolase targets of organophosphorus toxicants. Chem Biol Interact. 2005;157–158:277-83. doi: 10.1016/j.cbi.2005.10.036.
Xu J, Li Y, Chen WD, Xu Y, Yin L, Ge X, et al. Hepatic carboxylesterase 1 is essential for both normal and farnesoid X receptor-controlled lipid homeostasis. Hepatology. 2014;59(5):1761–71. doi: 10.1002/hep.26714.
Chen YT, Shi D, Yang D, Yan B. Antioxidant sulforaphane and sensitizer trinitrobenzene sulfonate induce carboxylesterase-1 through a novel element transactivated by nuclear factor-E2 related factor-2. Biochem. Pharmacol. 2012;84(6):864-71. doi: 10.1016/j.bcp.2012.06.025.
Fahey JW, Wade KL, Wehage SL, Holtzclaw WD, Liu H, Talalay P, et al. Stabilized sulforaphane for clinical use: Phytochemical delivery efficiency. Mol Nutr Food Res. 2017;61(4). doi: 10.1002/mnfr.201600766.
Zhu W, Song L, Zhang H, Matoney L, LeCluyse E, Yan B. Dexamethasone differentially regulates expression of carboxylesterase genes in humans and rats. Drug Metab Dispos. 2000;28(2):186-91. PMID: 10640517.
Edwards DJ. Beneficial Pharmacokinetic Drug Interactions. Adv Pharmacoepidem Drug Safety. 2012;1:002. doi: 10.4172/2167-1052.1000S1-002.
Paul A. Fixed-Dose Combinations. In: Raj G, Raveendran R, editors. Introduction to Basics of Pharmacology and Toxicology. Springer, Singapore; 2019. p. 307-12.
Heel RC, Brogden RN, Speight TM, Avery GS. Loperamide: a review of its pharmacological properties and therapeutic efficacy in diarrhoea. Drugs. 1978;15(1):33-52. doi: 10.2165/00003495-197815010-00003.
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