Biotransformation and Bioactivation

  • Siamak Cyrus Khojasteh
  • Harvey Wong
  • Cornelis E. C. A. Hop


The terms metabolism and biotransformation are used interchangeably in this book. As described in Chap. 2, metabolism is a major route of elimination of drugs from the body and, in general, results in the formation of metabolites that are more polar than the parent drug. Here, we discuss techniques for detection of metabolites, bioactivation and its ramifications, metabolites in drug safety studies, and what transformation happens to different common moieties in drugs as a result of metabolism.


Neutral Loss Covalent Binding Triple Quadrupole Mass Spectrometer Reactive Metabolite Idiosyncratic Toxicity 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

List of Abbreviations


Drug metabolizing enzyme


Double bond equivalent




Glutathione S-transferase




Hydrogen atom transfer


International Conference on Harmonisation


Liquid chromatography


Metabolites in safety testing


Mass spectroscopy


Nicotinamide adenine dinucleotide phosphate




Nuclear magnetic resonance


Cytochrome P450






Single electron transfer




  1. Argoti D, Liang L, Conteh A et al (2005) Cyanide trapping of iminium ion reactive intermediates followed by detection and structure identification using liquid chromatography−tandem mass spectrometry (LC-MS/MS). Chem Res Toxicol 18:1537PubMedCrossRefGoogle Scholar
  2. Dalvie D, Kang P, Zientek M et al (2008) Effect of intestinal glucuronidation in limiting hepatic exposure and bioactivation of raloxifene in humans and rats. Chem Res Toxicol 21:2260–2271PubMedCrossRefGoogle Scholar
  3. Day SH, Mao A, White R et al (2005) A semi-automated method for measuring the potential for protein covalent binding in drug discovery. J Pharmacol Toxicol Meth 52:278–285CrossRefGoogle Scholar
  4. Dieckhaus CM, Fernandez-Metzler CL, King R et al (2005) Negative ion tandem mass spectrometry for the detection of glutathione conjugates. Chem Res Toxicol 18:630–638PubMedCrossRefGoogle Scholar
  5. Evans DC, Watt AP, Nicoll-Griffith DA et al (2004) Drug–protein adducts: An industry perspective on minimizing the potential for drug bioactivation in drug discovery and development. Chem Res Toxicol 17:3–16PubMedCrossRefGoogle Scholar
  6. FDA (2008) US Food and Drug Administration guidance for industry: safety testing of drug metabolites. RegulatoryInformation/Guidances/ucm079266.pdf. Accessed 28 June 2010
  7. Frederick CB, Obach RS (2010) Metabolites in safety testing: “MIST” for the clinical pharmacologist. Clin Pharmacol Ther 87:345–350PubMedCrossRefGoogle Scholar
  8. Gan J, Ran Q, He B et al (2009) In vitro screening of 50 highly prescribed drugs for thiol adduct formation: comparison of potential for drug-induced toxicity and extent of adduct formation. Chem Res Toxicol 22:690–698PubMedCrossRefGoogle Scholar
  9. Hop CECA, Wang Z, Chen Q et al (1998) Plasma-pooling methods to increase throughput for in vivo pharmacokinetic screening. J Pharm Sci 87:901–903PubMedCrossRefGoogle Scholar
  10. ICH Expert Working Group (2009) ICH harmonised tripartite guideline: guidance on nonclinical safety studies for the conduct of human clinical trials and marketing authorization for pharmaceuticals M3(R2). Accessed 28 June 2010
  11. Ju C, Uetrecht JP (2002) Mechanism of idiosyncratic drug reactions: reactive metabolites formation, protein binding and the regulation of the immune system. Curr Drug Metab 3:367–377PubMedCrossRefGoogle Scholar
  12. Kalgutkar AS, Soglia JR (2005) Minimising the potential for metabolic activation in drug discovery. Expert Opin Drug Metab Toxicol 1:91–142PubMedCrossRefGoogle Scholar
  13. Kaiser J-P, Feng Y, Bollag J-M (1996) Microbial metabolism of pyridine, quinoline, acridine, and their derivatives under aerobic and anaerobic conditions. Microbiol Rev 60:483–498PubMedGoogle Scholar
  14. Kola I, Landis J (2004) Can the pharmaceutical industry reduce attrition rates? Nat Rev Drug Disc 3:711–715CrossRefGoogle Scholar
  15. Liu DQ, Hop CECA (2005) Strategies for characterization of drug metabolites using liquid chromatography–tandem mass spectrometry in conjunction with chemical derivatization and on-line H/D exchange approaches. J Pharm Biomed Anal 37:1–18PubMedCrossRefGoogle Scholar
  16. Mutlib AE, Gerson RJ, Meunier PC et al (2000) The species-dependent metabolism of efavirenz produces a nephrotoxic glutathione conjugate in rats. Toxicol Appl Pharmacol 169:102–113PubMedCrossRefGoogle Scholar
  17. Obach RS, Kalgutkar AS, Soglia JR et al (2008) Can in vitro metabolism-dependent covalent binding data in liver microsomes distinguish hepatotoxic from nonhepatotoxic drugs? An analysis of 18 drugs with consideration of intrinsic clearance and daily dose. Chem Res Toxicol 21:1814–1822PubMedCrossRefGoogle Scholar
  18. Ozer JS, Dieterle F, Troth S et al (2010) A panel of urinary biomarkers to monito reversibility of renal injury and a serum marker with improved potential to assess renal function. Nat Biotechnol 28:486–494PubMedCrossRefGoogle Scholar
  19. Roberts KM, Jones JP (2010) Anilinic N-oxides support cytochrome P450-mediated N-dealkylation through hydrogen-atom transfer. Chemistry 16:8096–8107PubMedGoogle Scholar
  20. Soglia JR, Contillo LG, Kalgutkar AS et al (2006) A semiquantitative method for the determination of reactive metabolite conjugate levels in vitro utilizing liquid chromatography−tandem mass spectrometry and novel quaternary ammonium glutathione analogues. Chem Res Toxicol 19:480–490PubMedCrossRefGoogle Scholar
  21. Testa B, Caldwell J (1994) The metabolism of drugs and other xenobiotics. Biochemistry of redox reactions (metabolism of drugs and other xenobiotics). Academic Press, San Diego, CAGoogle Scholar
  22. Thompson DC, Perera K, London R (1995) Quinone methide formation from para isomers of methylphenol (cresol), ethylphenol, and isopropylphenol: relationship to toxicity. Chem Res Toxicol 8:55–60PubMedCrossRefGoogle Scholar
  23. Uetrecht JP (2002) Preface. Curr Drug Metab 3:i–i(1)CrossRefGoogle Scholar
  24. Vishwanathan K, Babalola K, Wang J et al (2009) Obtaining exposures of metabolites in preclinical species through plasma pooling and quantitative NMR: addressing metabolites in Safety Testing (MIST) guidance without using radiolabeled compounds and chemically synthesized metabolite standards. Chem Res Toxicol 22:311–322PubMedCrossRefGoogle Scholar
  25. Walker D, Brady J, Dalvie D et al (2009) A holistic strategy for characterizing the safety of metabolites through drug discovery and development. Chem Res Toxicol 22:1653–1662PubMedCrossRefGoogle Scholar
  26. Yan Z, Caldwell GW (2004) Stable-isotope trapping and high-throughput screenings of reactive metabolites using the isotope MS signature. Anal Chem 76:6835–6847PubMedCrossRefGoogle Scholar

Additional Reading

  1. See Chap. 2Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Siamak Cyrus Khojasteh
    • 1
  • Harvey Wong
    • 1
  • Cornelis E. C. A. Hop
    • 1
  1. 1.Genentech, Inc.San FranciscoUSA

Personalised recommendations