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Drug Metabolism

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ADME Processes in Pharmaceutical Sciences

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Abstract

Living systems have developed elimination mechanisms to dispose waste products and to protect themselves from exposure to potentially harmful chemical compounds. Protective strategies to limit such exposure include the existence of biological barriers with selective permeability, the chemical disposal of xenobiotics by chemical biotransformations, and the physical disposal of xenobiotics (or its biotransformation products) through excretion routes. This chapter discusses the enzymatic systems involved in drug metabolism and the strong integration of these systems with other elimination mechanisms.

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References

  • Badenhorst CP, van der Sluis R, Erasmus E, van Dijk AA (2013) Glycine conjugation: importance in metabolism, the role of glycine N-acyltransferase, and factors that influence interindividual variation. Expert Opin Drug Metab Toxicol 9:1139–1153

    Article  CAS  Google Scholar 

  • Bray GP, Harrison PM, O’Grady JG, Tredger JM, Williams R (1992) Long-term anticonvulsant therapy worsens outcome in paracetamol-induced fulminant hepatic failure. Hum Exp Toxicol 11:265–270

    Article  CAS  Google Scholar 

  • Bu H, (2006) A Literature Review of Enzyme Kinetic Parameters for CYP3A4-Mediated MetabolicReactions of 113 Drugs in Human Liver Microsomes: Structure- Kinetics Relationship Assessment. Current Drug Metabolism 7 (3):231-249

    Google Scholar 

  • Castellano I, Novillo R, Gómez-Martino JR, Covarsi A, Herrero JL (2001) Fracaso renal agudo debido a intoxicación por paracetamol. Nefrologia (Madr) 21:592–595

    Google Scholar 

  • Caparrotta TM, Antoine DJ, Dear JW (2018) Are some people at increased risk of paracetamol-induced liver injury? A critical review of the literature. Eur J Clin Pharmacol 74:147–160

    Article  CAS  Google Scholar 

  • Cribb AE, Peyrou M, Muruganandan S (2005) The endoplasmic reticulum in xenobiotic toxicity. Drug Metab Rev 37:405–442

    Article  CAS  Google Scholar 

  • Day S et al., (2017) Stratified, precision or personalised medicine? Cancer services in the ‘real world’ of a London hospital. Sociol Health Illn. 39(1):143–158. https://doi.org/10.1111/1467-9566.12457

  • Daly FFS, Fountain JS, Murray L, Graudins A, Buckley NA (2008) Guidelines for the management of paracetamol poisoning in Australia and New Zealand — explanation and elaboration. Med J Aust 188:296–302

    PubMed  Google Scholar 

  • Fathi M, Kazemi S, Zahedi F, Shiran MR, Moghadamnia AA (2018) Comparison of oral bioavailability of acetaminophen tablets, capsules and effervescent dosage forms in healthy volunteers. Curr Issues Pharm Med Sci 31:5–9

    Article  CAS  Google Scholar 

  • Fura A (2006) Role of pharmacologically active metabolites in drug discovery and development. Drug Discov Today 11:133–142

    Article  CAS  Google Scholar 

  • Furge LL, Guenguerich FP (2006) Cytochrome P450 enzymes in drug metabolism and chemical toxicology: an introduction. Biochem Mol Biol Educ 34:66–74

    Article  CAS  Google Scholar 

  • Gan L, von Moltke LL, Trepanier LA, Harmatz JS, Greenblatt DJ, Court MH (2009) Role of NADPH-cytochrome P450 reductase and cytochrome-b5/NADH-b5 reductase in variability of CYP3A activity in human liver microsomes. Drug Metab Dispos 37:90–96

    Article  CAS  Google Scholar 

  • Gan J, Zhang H, Humphreys WG (2016) Drug-protein adducts: chemistry, mechanisms of toxicity, and methods of characterization. Chem Res Toxicol 29:2040–2057

    Article  CAS  Google Scholar 

  • Gibbons GF (2002) The role of cytochrome P450 in the regulation of cholesterol biosynthesis. Lipids 37:1163–1170

    Article  CAS  Google Scholar 

  • Guengerich FP (2001) Common and uncommon cytochrome P450 reactions related to metabolism and chemical toxicity. Chem Res Toxicol 14:611–650

    Article  CAS  Google Scholar 

  • Guengerich FP (2007) Mechanisms of cytochrome P450 substrate oxidation: MiniReview. J Biochem Mol Toxicol 21:163–168

    Article  CAS  Google Scholar 

  • Homolya L, Váradi A, Sarkadi B (2003) Multidrug resistance-associated proteins: export pumps for conjugates with glutathione, glucuronate or sulfate. Biofactors 17:103–114

    Article  CAS  Google Scholar 

  • Jennen DGJ, Gaj S, Giestbertz PJ, van Delft JHM, Evelo CT, Kleinjans JCS (2010) Biotransformation pathway maps in WikiPathways enable direct visualization of drug metabolism related expression changes. Drug Discov Today 15:851–858

    Article  CAS  Google Scholar 

  • Jenner P, Testa B, Di Carlo FJ (1981) Xenobiotic and endobiotic metabolizing enzymes: an overstretched discrimination? Trends Pharmacol Sci 2:135–137

    Article  CAS  Google Scholar 

  • Jones G, Prosser DE, Kaufmann M (2014) Cytochrome P450-mediated metabolism of vitamin D. J Lipid Res 55:13–31

    Article  CAS  Google Scholar 

  • Kolár M, Fanfrlík J, Hobza P (2011) Ligand conformational and solvation/desolvation free energy in protein-ligand complex formation. J Phys Chem B 115:4718–4724

    Article  Google Scholar 

  • Krämer SD, Testa B (2008) The biochemistry of drug metabolism – an introduction. Part 6. Inter-individual factors affecting drug metabolism. Chem Biodivers 5:2465–2573

    Article  Google Scholar 

  • Krämer SD, Testa B (2009) The biochemistry of drug metabolism – an introduction. Part 6. Intra-individual factors affecting drug metabolism. Chem Biodivers 6:1477–1660

    Article  Google Scholar 

  • Kurtovic J, Riordan SM, (2003) Paracetamol-induced hepatotoxicity at recommended dosage. Journal of Internal Medicine 253 (2):240–243

    Google Scholar 

  • Kwon Y (2002) Handbook of essentials pharmacokinetics, pharmacodynamics, and drug metabolism for industrial scientists. Kluwer Academic Publishers, New York

    Google Scholar 

  • Lauretti WJ (2012) In: Gatterman MI (ed) The safety and effectiveness of common treatments for whiplash. Elsevier Mosby, St. Louis

    Chapter  Google Scholar 

  • Lepesheva GI, Waterman MR (2011) Sterol 14alpha-demethylase (CYP51) as a therapeutic target for human trypanosomiasis and leishmaniasis. Curr Top Med Chem 11:2060–2071

    Article  CAS  Google Scholar 

  • Lepesheva GI, Friggeri L, Waterman MR (2018) CYP51 as drug targets for fungi and protozoan parasites: past, present and future. Parasitology 12:1–17

    Google Scholar 

  • Lewis DF (2004) 57 varieties: the human cytochromes P450. Pharmacogenomics 5:305–318

    Article  CAS  Google Scholar 

  • Liston HL, Markowitz JS, DeVane CL (2001) Drug glucuronidation in clinical psychopharmacology. J Clin Psycopharmacol 21:500–515

    Article  CAS  Google Scholar 

  • Liu Y, Ramírez J, Ratain MJ, (2011) Inhibition of paracetamol glucuronidation by tyrosine kinase inhibitors. British Journal of Clinical Pharmacology 71 (6):917–920

    Google Scholar 

  • Lynch T, Price A (2007) The effect of cytochrome P450 metabolism on drug response, interactions, and adverse effects. Am Fam Physician 76:391–396

    PubMed  Google Scholar 

  • Mahadevan SBK, McKiernan PJ, Davies P, Kelly DA (2006) Paracetamol induced hepatotoxicity. Arch Dis Child 91:598–603

    Article  CAS  Google Scholar 

  • Matias M, Canário C, Silvestre S, Falcao A, Alves G (2014) In: Wu J (ed) Cytochrome P450-mediated toxicity of therapeutic drugs. Nova Science Publishers, New York

    Google Scholar 

  • Meunier B, Samuël P, de Visser, Shaik S (2004) Mechanism of Oxidation Reactions Catalyzed by Cytochrome P450 Enzymes. Chemical Reviews 104 (9):3947–3980

    Google Scholar 

  • Nebert DW, Wikvall K, Miller WL (2013) Human cytochromes P450 in health and disease. Philos Trans R Soc Lond Ser B Biol Sci 368:20120431

    Article  Google Scholar 

  • Smith FC (2008) In: Pearson PG, Wienkers LC (eds) Pharmacokinetics of drug metabolites. Informa Healthcare, New York

    Google Scholar 

  • Swanson HI, (2015) Drug Metabolism by the Host and Gut Microbiota: A Partnership or Rivalry?. Drug Metabolism and Disposition 43 (10):1499–1504

    Google Scholar 

  • Talevi A (2016) The importance of bioactivation in computer-guided drug repositioning. Why the parent drug is not always enough. Curr Top Med Chem 16:2078–2087

    Article  CAS  Google Scholar 

  • Talevi A (2018) Drug repositioning: current approaches and their implications in the precision medicine era. Expert Review of Precision Medicine and Drug Development 3 (1):49–61

    Google Scholar 

  • Tang W, Lu AY (2010) Metabolic bioactivation and drug-related adverse effects: current status and future directions from a pharmaceutical research perspective. Drug Metab Rev 42:225–249

    Article  CAS  Google Scholar 

  • Testa B, Krämer SD (2006) The biochemistry of drug metabolism – an introduction. Part 1. Principles and overview. Chem Biodivers 3:1053–1101

    Article  CAS  Google Scholar 

  • Testa B, Krämer SD (2007) The biochemistry of drug metabolism – an introduction. Part 2. Redox reactions and their enzymes. Chem Biodivers 4:257–405

    Article  CAS  Google Scholar 

  • Testa B, Krämer SD (2008) The biochemistry of drug metabolism – an introduction. Part 4. Reactions of conjugation and their enzymes. Chem Biodivers 5:2171–2336

    Article  CAS  Google Scholar 

  • Testa B, Pedretti A, Vistoli G (2012) Foundation review: reactions and enzymes in the metabolism of drugs and other xenobiotics. Drug Discov Today 17:549–560

    Article  CAS  Google Scholar 

  • Tu BP, Weissman JS (2004) Oxidative protein folding in eukaryotes: mechanisms and consequences. J Cell Biol 164:341–346

    Article  CAS  Google Scholar 

  • Walsh JS, Miwa GT (2011) Bioactivation of drugs: risk and drug design. Annu Rev Pharmacol Toxicol 51:145–167

    Article  CAS  Google Scholar 

  • Westphal C, Konkel A, Schunck WH (2015) Cytochrome p450 enzymes in the bioactivation of polyunsaturated fatty acids and their role in cardiovascular disease. Adv Exp Med Biol 851:151–187

    Article  CAS  Google Scholar 

  • Williams JA, Hyland R, Jones BC, Smith DA, Gurst S, Goosen TC, Peterkin V, Koup JR, Ball SE (2004) Drug-drug interactions for UDP-glucuronosyltransferase substrates: a pharmacokinetic explanation for typically observed low exposure (AUCi/AUC) ratios. Drug Metab Dispos 32:1201–1208

    Article  CAS  Google Scholar 

  • Xiang Q, Zhao X, Zhou Y, Duan JL, Cui YM (2010) Effect of CYP2D6, CYP3A5, and MDR1 genetic polymorphisms on the pharmacokinetics of risperidone and its active moiety. J Clin Pharmacol 50:659–666

    Article  CAS  Google Scholar 

Further Reading

  • Drug metabolism is a vast topic, and entire books have been written about it. Here, we intended to provide a summary of the more relevant points of drug biotransformation, but the chapter is far from exhaustive. For a much deeper insight on the topic, the reader is advised to Pearson and Wienkers’s Handbook of Drug Metabolism (currently in its 3rd edition by CRC Press); the Drug Metabolism Handbook edited by Nassar, Hollenberg, and Scatina (2008, Wiley & Sons); and the extensive and unbelievably comprehensive series of articles by Testa and Krämer, many of which have been included in the reference list of the present chapter.

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Authors and Affiliations

  1. Laboratory of Bioactive Research and Development (LIDeB), Department of Biological Sciences, Faculty of Exact Sciences, University of La Plata (UNLP), La Plata, Buenos Aires, Argentina

    Carolina Leticia Bellera

  2. Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), La Plata, Buenos Aires, Argentina

    Carolina Leticia Bellera

  3. Medicinal Chemistry/Laboratory of Bioactive Research and Development (LIDeB), Faculty of Exact Sciences, Universidad Nacional de La Plata (UNLP), La Plata, Buenos Aires, Argentina

    Alan Talevi

  4. Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina

    Alan Talevi

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  1. Alan Talevi
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  2. Carolina Leticia Bellera
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Correspondence to Alan Talevi .

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Editors and Affiliations

  1. Laboratory of Bioactive Research and Development (LIDeB), Department of Biological Sciences, Faculty of Exact Sciences, University of La Plata (UNLP), La Plata, Buenos Aires, Argentina

    Alan Talevi

  2. Quality Control of Pharmaceutical Products, Pharmaceutical Toxicology, Department of Biological Sciences, Faculty of Exact Sciences, Universidad Nacional de La Plata, La Plata, Buenos Aires, Argentina

    Pablo A. M. Quiroga

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Talevi, A., Bellera, C.L. (2018). Drug Metabolism. In: Talevi, A., Quiroga, P. (eds) ADME Processes in Pharmaceutical Sciences. Springer, Cham. https://doi.org/10.1007/978-3-319-99593-9_4

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