Skip to main content
SpringerLink
Log in
Book cover

Adverse Drug Reactions pp 511–544Cite as

Approaches for Minimizing Metabolic Activation of New Drug Candidates in Drug Discovery

  • Chapter
  • First Online:

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 196))

Abstract

A large body of circumstantial evidence suggests that metabolic activation of drug candidates to chemically reactive electrophilic metabolites that are capable of covalently modifying cellular macromolecules may result in acute and/or immune system-mediated idiosyncratic toxicities in humans. Thus, minimizing the potential for metabolic activation of new drug candidates during the drug discovery and lead optimization stage represents a prudent strategy to help discover and develop the next generation of safe and effective therapeutic agents. In the present chapter, we discuss the scientific methodologies that currently are available to industrial pharmaceutical scientists for assessing and minimizing metabolic activation during drug discovery, their attributes and limitations, and future scientific directions that have the potential to help advance progress in this field. We also propose a roadmap that should help utilize the armamentarium of available scientific tools in a logical way and contribute to addressing metabolic activation issues in the drug discovery-setting in a rapid, scientifically appropriate, and resource-conscious manner.

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   299.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

Abbreviations

GSH:

Glutathione

KCN:

Potassium cyanide

TZD:

Thiazolidinedione

OZD:

Oxazolidinedione

References

  • Adams CP, Brantner VV (2006) Estimating the cost of new drug development: is it really 802 million dollars? Health Aff (Millwood) 25:420-428

    Google Scholar 

  • Alvarez-Sanchez R, Montavon F, Hartung T, Pahler A (2006) Thiazolidinedione bioactivation: a comparison of the bioactivation potentials of troglitazone, rosiglitazone, and pioglitazone using stable isotope-labeled analogues and liquid chromatography tandem mass spectrometry. Chem Res Toxicol 19:1106-1116

    PubMed  CAS  Google Scholar 

  • Argoti D, Liang L, Conteh A, Chen L, Bershas D, Yu CP, Vouros P, Yang E (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 18:1537-1544

    PubMed  CAS  Google Scholar 

  • Azuma H, Paulk N, Ranade A, Dorrell C, Al Dhalimy M, Ellis E, Strom S, Kay MA, Finegold M, Grompe M (2007) Robust expansion of human hepatocytes in Fah-/-/Rag2-/-/Il2rg-/- mice. Nat Biotechnol 25:903-910

    PubMed  CAS  Google Scholar 

  • Baillie TA (2006) Future of toxicology-metabolic activation and drug design: challenges and opportunities in chemical toxicology. Chem Res Toxicol 19:889-893

    PubMed  CAS  Google Scholar 

  • Baillie TA (2008) Metabolism and toxicity of drugs. Two decades of progress in industrial drug metabolism. Chem Res Toxicol 21:129-137

    PubMed  Google Scholar 

  • Baillie TA, Davis MR (1993) Mass spectrometry in the analysis of glutathione conjugates. Biol Mass Spectrom 22:319-325

    PubMed  CAS  Google Scholar 

  • Bateman KP, Castro-Perez J, Wrona M, Shockcor JP, Yu K, Oballa R, Nicoll-Griffith DA (2007) MSE with mass defect filtering for in vitro and in vivo metabolite identification. Rapid Commun Mass Spectrom 21:1485-1496

    PubMed  CAS  Google Scholar 

  • Baudoin R, Corlu A, Griscom L, Legallais C, Leclerc E (2007) Trends in the development of microfluidic cell biochips for in vitro hepatotoxicity. Toxicol In Vitro 21:535-544

    PubMed  CAS  Google Scholar 

  • Boelsterli UA, Ho HK, Zhou S, Leow KY (2006) Bioactivation and hepatotoxicity of nitroaromatic drugs. Curr Drug Metab 7:715-727

    PubMed  CAS  Google Scholar 

  • Bolton JL, Trush MA, Penning TM, Dryhurst G, Monks TJ (2000) Role of quinones in toxicology. Chem Res Toxicol 13:135-160

    PubMed  CAS  Google Scholar 

  • Castro-Perez J, Plumb R, Liang L, Yang E (2005) A high-throughput liquid chromatography/tandem mass spectrometry method for screening glutathione conjugates using exact mass neutral loss acquisition. Rapid Commun Mass Spectrom 19:798-804

    PubMed  CAS  Google Scholar 

  • Chauret N, Guay D, Li C, Day S, Silva J, Blouin M, Ducharme Y, Yergey JA, Nicoll-Griffith DA (2002) Improving metabolic stability of phosphodiesterase-4 inhibitors containing a substituted catechol: prevention of reactive intermediate formation and covalent binding. Bioorg Med Chem Lett 12:2149-2152

    PubMed  CAS  Google Scholar 

  • Chen WG, Zhang C, Avery MJ, Fouda HG (2001) Reactive metabolite screen for reducing candidate attrition in drug discovery. In: Biological Reactive Intermediates VI: Chemical and Biological Mechanisms in Susceptibility to and Prevention of Environmental Diseases, Dansette PM, Snyder R, Delaforge M, Gibson GG, Greim H, Jollow DJ, Monks TJ, Sipes IG (eds.). Kluwer Academic/Plenum Press: New York 521-524

    Google Scholar 

  • Chen LJ, DeRose EF, Burka LT (2006) Metabolism of furans in vitro: ipomeanine and 4-ipomeanol. Chem Res Toxicol 19:1320-1329

    PubMed  CAS  Google Scholar 

  • Dalvie DK, Kalgutkar AS, Khojasteh-Bakht SC, Obach RS, O'Donnell JP (2002) Biotransformation reactions of five-membered aromatic heterocyclic rings. Chem Res Toxicol 15:269-299

    PubMed  CAS  Google Scholar 

  • Day SH, Mao A, White R, Schulz-Utermoehl T, Miller R, Beconi MG (2005) A semi-automated method for measuring the potential for protein covalent binding in drug discovery. J Pharmacol Toxicol Methods 52:278-285

    PubMed  CAS  Google Scholar 

  • Dennehy MK, Richards KA, Wernke GR, Shyr Y, Liebler DC (2006) Cytosolic and nuclear protein targets of thiol-reactive electrophiles. Chem Res Toxicol 19:20-29

    PubMed  CAS  Google Scholar 

  • Dieckhaus CM, Fernandez-Metzler CL, King R, Krolikowski PH, Baillie TA (2005) Negative ion tandem mass spectrometry for the detection of glutathione conjugates. Chem Res Toxicol 18:630-638

    PubMed  CAS  Google Scholar 

  • DiMasi JA, Hansen RW, Grabowski HG (2003) The price of innovation: new estimates of drug development costs. J Health Econ 22:151-185

    PubMed  Google Scholar 

  • Doss GA, Miller RR, Zhang Z, Teffera Y, Nargund RP, Palucki B, Park MK, Tang YS, Evans DC, Baillie TA, Stearns RA (2005) Metabolic activation of a 1, 3-disubstituted piperazine derivative: evidence for a novel ring contraction to an imidazoline. Chem Res Toxicol 18:271-276

    PubMed  CAS  Google Scholar 

  • Erve JC (2006) Chemical toxicology: reactive intermediates and their role in pharmacology and toxicology. Expert Opin Drug Metab Toxicol 2:923-946

    PubMed  CAS  Google Scholar 

  • Evans DC, Baillie TA (2005) Minimizing the potential for metabolic activation as an integral part of drug design. Curr Opin Drug Discov Dev 8:44-50

    CAS  Google Scholar 

  • Evans DC, Watt AP, Nicoll-Griffith DA, Baillie TA (2004) Drug-protein adducts: an industry perspective on minimizing the potential for drug bioactivation in drug discovery and development. Chem Res Toxicol 17:3-16

    PubMed  CAS  Google Scholar 

  • Gan J, Harper TW, Hsueh MM, Qu Q, Humphreys WG (2005) Dansyl glutathione as a trapping agent for the quantitative estimation and identification of reactive metabolites. Chem Res Toxicol 18:896-903

    PubMed  CAS  Google Scholar 

  • Gatzidou ET, Zira AN, Theocharis SE (2007) Toxicogenomics: a pivotal piece in the puzzle of toxicological research. J Appl Toxicol 27:302-309

    PubMed  CAS  Google Scholar 

  • Gorrod JW, Whittlesea CM, Lam SP (1991) Trapping of reactive intermediates by incorporation of 14C-sodium cyanide during microsomal oxidation. Adv Exp Med Biol 283:657-664

    PubMed  CAS  Google Scholar 

  • Grillo MP, Hua F, Knutson CG, Ware JA, Li C (2003a) Mechanistic studies on the bioactivation of diclofenac: identification of diclofenac-S-acyl-glutathione in vitro in incubations with rat and human hepatocytes. Chem Res Toxicol 16:1410-1417

    PubMed  CAS  Google Scholar 

  • Grillo MP, Knutson CG, Sanders PE, Waldon DJ, Hua F, Ware JA (2003b) Studies on the chemical reactivity of diclofenac acyl glucuronide with glutathione: identification of diclofenac-S-acyl-glutathione in rat bile. Drug Metab Dispos 31:1327-1336

    PubMed  CAS  Google Scholar 

  • Hanzlik RP, Koen YM, Theertham B, Dong Y, Fang J (2007) The reactive metabolite target protein database (TPDB)-a web-accessible resource. BMC Bioinformat 8:95

    Google Scholar 

  • He K, Iyer KR, Hayes RN, Sinz MW, Woolf TF, Hollenberg PF (1998) Inactivation of cytochrome P450 3A4 by bergamottin, a component of grapefruit juice. Chem Res Toxicol 11:252-259

    PubMed  CAS  Google Scholar 

  • Jushchyshyn MI, Kent UM, Hollenberg PF (2003) The mechanism-based inactivation of human cytochrome P450 2B6 by phencyclidine. Drug Metab Dispos 31:46-52

    PubMed  CAS  Google Scholar 

  • Jushchyshyn MI, Wahlstrom JL, Hollenberg PF, Wienkers LC (2006) Mechanism of inactivation of human cytochrome P450 2B6 by phencyclidine. Drug Metab Dispos 34:1523-1529

    PubMed  CAS  Google Scholar 

  • Kalgutkar AS, Soglia JR (2005) Minimising the potential for metabolic activation in drug discovery. Expert Opin Drug Metab Toxicol 1:91-142

    PubMed  CAS  Google Scholar 

  • Kalgutkar AS, Dalvie DK, O'Donnell JP, Taylor TJ, Sahakian DC (2002) On the diversity of oxidative bioactivation reactions on nitrogen-containing xenobiotics. Curr Drug Metab 3:379-424

    PubMed  CAS  Google Scholar 

  • Kalgutkar AS, Gardner I, Obach RS, Shaffer CL, Callegari E, Henne KR, Mutlib AE, Dalvie DK, Lee JS, Nakai Y, O'Donnell JP, Boer J, Harriman SP (2005) A comprehensive listing of bioactivation pathways of organic functional groups. Curr Drug Metab 6:161-225

    PubMed  CAS  Google Scholar 

  • Kalgutkar AS, Dalvie DK, Aubrecht J, Smith EB, Coffing SL, Cheung JR, Vage C, Lame ME, Chiang P, McClure KF, Maurer TS, Coelho RV Jr, Soliman VF, Schildknegt K (2007a) Genotoxicity of 2-(3-chlorobenzyloxy)-6-(piperazinyl) pyrazine, a novel 5-hydroxytryptamine2c receptor agonist for the treatment of obesity: role of metabolic activation. Drug Metab Dispos 35:848-858

    PubMed  CAS  Google Scholar 

  • Kalgutkar AS, Obach RS, Maurer TS (2007b) Mechanism-based inactivation of cytochrome P450 enzymes: chemical mechanisms, structure-activity relationships and relationship to clinical drug-drug interactions and idiosyncratic adverse drug reactions. Curr Drug Metab 8:407-447

    PubMed  CAS  Google Scholar 

  • Kassahun K, Pearson PG, Tang W, McIntosh I, Leung K, Elmore C, Dean D, Wang R, Doss G, Baillie TA (2001) Studies on the metabolism of troglitazone to reactive intermediates in vitro and in vivo. Evidence for novel biotransformation pathways involving quinone methide formation and thiazolidinedione ring scission. Chem Res Toxicol 14:62-70

    PubMed  CAS  Google Scholar 

  • Katoh M, Yokoi T (2007) Application of chimeric mice with humanized liver for predictive ADME. Drug Metab Rev 39:145-157

    PubMed  CAS  Google Scholar 

  • Katoh M, Sawada T, Soeno Y, Nakajima M, Tateno C, Yoshizato K, Yokoi T (2007) In vivo drug metabolism model for human cytochrome P450 enzyme using chimeric mice with humanized liver. J Pharm Sci 96:428-437

    PubMed  CAS  Google Scholar 

  • Khetani SR, Bhatia SN (2006) Engineering tissues for in vitro applications. Curr Opin Biotechnol 17:524-531

    PubMed  CAS  Google Scholar 

  • Khetani SR, Bhatia SN (2008) Microscale culture of human liver cells for drug development. Nat Biotechnol 26:120-126

    PubMed  CAS  Google Scholar 

  • Khojasteh-Bakht SC, Chen W, Koenigs LL, Peter RM, Nelson SD (1999) Metabolism of (R)-(+)-pulegone and (R)-(+)-menthofuran by human liver cytochrome P-450s: evidence for formation of a furan epoxide. Drug Metab Dispos 27:574-580

    PubMed  CAS  Google Scholar 

  • Koen YM, Gogichaeva NV, Alterman MA, Hanzlik RP (2007) A proteomic analysis of bromobenzene reactive metabolite targets in rat liver cytosol in vivo. Chem Res Toxicol 20:511-519

    PubMed  CAS  Google Scholar 

  • Kolbanovskiy A, Kuzmin V, Shastry A, Kolbanovskaya M, Chen D, Chang M, Bolton JL, Geacintov NE (2005) Base selectivity and effects of sequence and DNA secondary structure on the formation of covalent adducts derived from the equine estrogen metabolite 4-hydroxyequilenin. Chem Res Toxicol 18:1737-1747

    PubMed  CAS  Google Scholar 

  • Kumar S, Kassahun K, Tschirret-Guth RA, Mitra K, Baillie TA (2008) Minimizing metabolic activation during pharmaceutical lead optimization: Progress, knowledge gaps and future directions. Curr Opin Drug Discov Dev 11:43-52

    CAS  Google Scholar 

  • Levesque JF, Day SH, Chauret N, Seto C, Trimble L, Bateman KP, Silva JM, Berthelette C, Lachance N, Boyd M, Li L, Sturino CF, Wang Z, Zamboni R, Young RN, Nicoll-Griffith DA (2007) Metabolic activation of indole-containing prostaglandin D2 receptor 1 antagonists: impacts of glutathione trapping and glucuronide conjugation on covalent binding. Bioorg Med Chem Lett 17:3038-3043

    PubMed  CAS  Google Scholar 

  • Li C, Grillo MP, Benet LZ (2003a) In vivo mechanistic studies on the metabolic activation of 2-phenylpropionic acid in rat. J Pharmacol Exp Ther 305:250-256

    PubMed  CAS  Google Scholar 

  • Li C, Olurinde MO, Hodges LM, Grillo MP, Benet LZ (2003b) Covalent binding of 2-phenylpropionyl-S-acyl-CoA thioester to tissue proteins in vitro. Drug Metab Dispos 31: 727-730

    PubMed  CAS  Google Scholar 

  • Liebler DC (2008) Protein damage by reactive electrophiles: targets and consequences. Chem Res Toxicol 21:117-128

    PubMed  CAS  Google Scholar 

  • Liebler DC, Guengerich FP (2005) Elucidating mechanisms of drug-induced toxicity. Nat Rev Drug Discov 4:410-420

    PubMed  CAS  Google Scholar 

  • Lin HL, Kent UM, Hollenberg PF (2005) The grapefruit juice effect is not limited to cytochrome P450 (P450) 3A4: evidence for bergamottin-dependent inactivation, heme destruction, and covalent binding to protein in P450s 2B6 and 3A5. J Pharmacol Exp Ther 313:154-164

    PubMed  CAS  Google Scholar 

  • Liu X, Pisha E, Tonetti DA, Yao D, Li Y, Yao J, Burdette JE, Bolton JL (2003) Antiestrogenic and DNA damaging effects induced by tamoxifen and toremifene metabolites. Chem Res Toxicol 16:832-837

    PubMed  CAS  Google Scholar 

  • Liu H, Liu J, van Breemen RB, Thatcher GR, Bolton JL (2005a) Bioactivation of the selective estrogen receptor modulator desmethylated arzoxifene to quinoids: 4′-fluoro substitution prevents quinoid formation. Chem Res Toxicol 18:162-173

    PubMed  Google Scholar 

  • Liu J, Liu H, van Breemen RB, Thatcher GR, Bolton JL (2005b) Bioactivation of the selective estrogen receptor modulator acolbifene to quinone methides. Chem Res Toxicol 18:174-182

    PubMed  CAS  Google Scholar 

  • Masubuchi Y (2006) Metabolic and non-metabolic factors determining troglitazone hepatotoxicity: a review. Drug Metab Pharmacokinet 21:347-356

    PubMed  CAS  Google Scholar 

  • Masubuchi Y, Horie T (2007) Toxicological significance of mechanism-based inactivation of cytochrome p450 enzymes by drugs. Crit Rev Toxicol 37:389-412

    PubMed  CAS  Google Scholar 

  • Masubuchi N, Makino C, Murayama N (2007) Prediction of in vivo potential for metabolic activation of drugs into chemically reactive intermediate: correlation of in vitro and in vivo generation of reactive intermediates and in vitro glutathione conjugate formation in rats and human. Chem Res Toxicol 20:455-464

    PubMed  CAS  Google Scholar 

  • Meneses-Lorente G, Sakatis MZ, Schulz-Utermoehl T, De Nardi C, Watt AP (2006) A quantitative high-throughput trapping assay as a measurement of potential for bioactivation. Anal Biochem 351:266-272

    PubMed  CAS  Google Scholar 

  • Miller JA (1994) Brief history of chemical carcinogenesis. Cancer Lett 83:9-14

    PubMed  CAS  Google Scholar 

  • Miller JA (1998) The metabolism of xenobiotics to reactive electrophiles in chemical carcinogenesis and mutagenesis: a collaboration with Elizabeth Cavert Miller and our associates. Drug Metab Rev 30:645-674

    PubMed  CAS  Google Scholar 

  • Mutlib AE, Chen H, Nemeth GA, Markwalder JA, Seitz SP, Gan LS, Christ DD (1999) Identification and characterization of efavirenz metabolites by liquid chromatography/mass spectrometry and high field NMR: species differences in the metabolism of efavirenz. Drug Metab Dispos 27:1319-1333

    PubMed  CAS  Google Scholar 

  • Mutlib AE, Gerson RJ, Meunier PC, Haley PJ, Chen H, Gan LS, Davies MH, Gemzik B, Christ DD, Krahn DF, Markwalder JA, Seitz SP, Robertson RT, Miwa GT (2000) The species-dependent metabolism of efavirenz produces a nephrotoxic glutathione conjugate in rats. Toxicol Appl Pharmacol 169:102-113

    PubMed  CAS  Google Scholar 

  • Mutlib A, Lam W, Atherton J, Chen H, Galatsis P, Stolle W (2005) Application of stable isotope labeled glutathione and rapid scanning mass spectrometers in detecting and characterizing reactive metabolites. Rapid Commun Mass Spectrom 19:3482-3492

    PubMed  CAS  Google Scholar 

  • Nassar AE, Lopez-Anaya A (2004) Strategies for dealing with reactive intermediates in drug discovery and development. Curr Opin Drug Discov Dev 7:126-136

    CAS  Google Scholar 

  • Nelson SD (2001) Structure toxicity relationships-how useful are they in predicting toxicities of new drugs? Adv Exp Med Biol 500:33-43

    PubMed  CAS  Google Scholar 

  • Olsen J, Li C, Bjornsdottir I, Sidenius U, Hansen SH, Benet LZ (2005) In vitro and in vivo studies on acyl-coenzyme A-dependent bioactivation of zomepirac in rats. Chem Res Toxicol 18:1729-1736

    PubMed  CAS  Google Scholar 

  • Olsen J, Li C, Skonberg C, Bjornsdottir I, Sidenius U, Benet LZ, Hansen SH (2007) Studies on the metabolism of tolmetin to the chemically reactive acyl-coenzyme A thioester intermediate in rats. Drug Metab Dispos 35:758-764

    PubMed  CAS  Google Scholar 

  • Park K, Williams DP, Naisbitt DJ, Kitteringham NR, Pirmohamed M (2005) Investigation of toxic metabolites during drug development. Toxicol Appl Pharmacol 207:425-434

    PubMed  Google Scholar 

  • Park KB, Dalton-Brown E, Hirst C, Williams DP (2006) Selection of new chemical entities with decreased potential for adverse drug reactions. Eur J Pharmacol 549:1-8

    PubMed  CAS  Google Scholar 

  • Peterson LA (2006) Electrophilic intermediates produced by bioactivation of furan. Drug Metab Rev 38:615-626

    PubMed  CAS  Google Scholar 

  • Potter WZ, Davis DC, Mitchell JR, Jollow DJ, Gillette JR, Brodie BB (1973) Acetaminophen-induced hepatic necrosis. 3. Cytochrome P-450-mediated covalent binding in vitro. J Pharmacol Exp Ther 187:203-210

    PubMed  CAS  Google Scholar 

  • Potter WZ, Thorgeirsson SS, Jollow DJ, Mitchell JR (1974) Acetaminophen-induced hepatic necrosis. V. Correlation of hepatic necrosis, covalent binding and glutathione depletion in hamsters. Pharmacology 12:129-143

    PubMed  CAS  Google Scholar 

  • Ruan Q, Peterman S, Szewc MA, Ma L, Cui D, Humphreys WG, Zhu M (2008) An integrated method for metabolite detection and identification using a linear ion trap/Orbitrap mass spectrometer and multiple data processing techniques: application to indinavir metabolite detection. J Mass Spectrom 43:251-261

    Google Scholar 

  • Sahali-Sahly Y, Balani SK, Lin JH, Baillie TA (1996) In vitro studies on the metabolic activation of the furanopyridine L-754, 394, a highly potent and selective mechanism-based inhibitor of cytochrome P450 3A4. Chem Res Toxicol 9:1007-1012

    PubMed  CAS  Google Scholar 

  • Samuel K, Yin W, Stearns RA, Tang YS, Chaudhary AG, Jewell JP, Lanza T Jr, Lin LS, Hagmann WK, Evans DC, Kumar S (2003) Addressing the metabolic activation potential of new leads in drug discovery: a case study using ion trap mass spectrometry and tritium labeling techniques. J Mass Spectrom 38:211-221

    PubMed  CAS  Google Scholar 

  • Senekeo-Effenberger K, Chen S, Brace-Sinnokrak E, Bonzo JA, Yueh MF, Argikar U, Kaeding J, Trottier J, Remmel RP, Ritter JK, Barbier O, Tukey RH (2007) Expression of the human UGT1 locus in transgenic mice by 4-chloro-6-(2, 3-xylidino)-2-pyrimidinylthioacetic acid (WY-14643) and implications on drug metabolism through peroxisome proliferator-activated receptor alpha activation. Drug Metab Dispos 35:419-427

    PubMed  CAS  Google Scholar 

  • Shibutani S, Ravindernath A, Suzuki N, Terashima I, Sugarman SM, Grollman AP, Pearl ML (2000) Identification of tamoxifen-DNA adducts in the endometrium of women treated with tamoxifen. Carcinogenesis 21:1461-1467

    PubMed  CAS  Google Scholar 

  • Shin NY, Liu Q, Stamer SL, Liebler DC (2007) Protein targets of reactive electrophiles in human liver microsomes. Chem Res Toxicol 20:859-867

    PubMed  CAS  Google Scholar 

  • Singh R, Silva Elipe MV, Pearson PG, Arison BH, Wong BK, White R, Yu X, Burgey CS, Lin JH, Baillie TA (2003) Metabolic activation of a pyrazinone-containing thrombin inhibitor. Evidence for novel biotransformation involving pyrazinone ring oxidation, rearrangement, and covalent binding to proteins. Chem Res Toxicol 16:198-207

    PubMed  CAS  Google Scholar 

  • Sivaraman A, Leach JK, Townsend S, Iida T, Hogan BJ, Stolz DB, Fry R, Samson LD, Tannenbaum SR, Griffith LG (2005) A microscale in vitro physiological model of the liver: predictive screens for drug metabolism and enzyme induction. Curr Drug Metab 6:569-591

    PubMed  CAS  Google Scholar 

  • Smith MT (2003) Mechanisms of troglitazone hepatotoxicity. Chem Res Toxicol 16:679-687

    PubMed  CAS  Google Scholar 

  • Soglia JR, Contillo LG, Kalgutkar AS, Zhao S, Hop CE, Boyd JG, Cole MJ (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 19:480-490

    PubMed  CAS  Google Scholar 

  • Stachulski AV (2007) The chemistry and biological activity of acyl glucuronides. Curr Opin Drug Discov Dev 10:58-66

    CAS  Google Scholar 

  • Tang W (2007) Drug metabolite profiling and elucidation of drug-induced hepatotoxicity. Expert Opin Drug Metab Toxicol 3:407-420

    PubMed  CAS  Google Scholar 

  • Tang C, Subramanian R, Kuo Y, Krymgold S, Lu P, Kuduk SD, Ng C, Feng DM, Elmore C, Soli E, Ho J, Bock MG, Baillie TA, Prueksaritanont T (2005) Bioactivation of 2,3-diaminopyridine-containing bradykinin B1 receptor antagonists: irreversible binding to liver microsomal proteins and formation of glutathione conjugates. Chem Res Toxicol 18:934-945

    PubMed  CAS  Google Scholar 

  • Tarloff JB, Khairallah EA, Cohen SD, Goldstein RS (1996) Sex- and age-dependent acetaminophen hepato- and nephrotoxicity in Sprague-Dawley rats: role of tissue accumulation, nonprotein sulfhydryl depletion, and covalent binding. Fundam Appl Toxicol 30:13-22

    PubMed  CAS  Google Scholar 

  • Tassaneeyakul W, Guo LQ, Fukuda K, Ohta T, Yamazoe Y (2000) Inhibition selectivity of grapefruit juice components on human cytochromes P450. Arch Biochem Biophys 378:356-363

    PubMed  CAS  Google Scholar 

  • Uetrecht J (2006) Evaluation of which reactive metabolite, if any, is responsible for a specific idiosyncratic reaction. Drug Metab Rev 38:745-753

    PubMed  CAS  Google Scholar 

  • Uetrecht J (2007) Idiosyncratic drug reactions: current understanding. Annu Rev Pharmacol Toxicol 47:513-539

    PubMed  CAS  Google Scholar 

  • Uetrecht J (2008) Idiosyncratic drug reactions: past, present, and future. Chem Res Toxicol 21:84-92

    PubMed  CAS  Google Scholar 

  • van Herwaarden AE, Smit JW, Sparidans RW, Wagenaar E, van der Kruijssen CM, Schellens JH, Beijnen JH, Schinkel AH (2005) Midazolam and cyclosporin a metabolism in transgenic mice with liver-specific expression of human CYP3A4. Drug Metab Dispos 33:892-895

    PubMed  Google Scholar 

  • van Waterschoot RA, van Herwaarden AE, Lagas JS, Sparidans RW, Wagenaar E, van der Kruijssen CM, Goldstein JA, Zeldin DC, Beijnen JH, Schinkel AH (2007) Midazolam metabolism in Cytochrome P450 3A knockout mice can be attributed to upregulated CYP2C enzymes. Mol Pharmacol 73:1029-1036

    Google Scholar 

  • Woods CG, Heuvel JP, Rusyn I (2007) Genomic profiling in nuclear receptor-mediated toxicity. Toxicol Pathol 35:474-494

    PubMed  CAS  Google Scholar 

  • Yan Z, Caldwell GW (2004) Stable-isotope trapping and high-throughput screenings of reactive metabolites using the isotope MS signature. Anal Chem 76:6835-6847

    PubMed  CAS  Google Scholar 

  • Yan Z, Maher N, Torres R, Caldwell GW, Huebert N (2005) Rapid detection and characterization of minor reactive metabolites using stable-isotope trapping in combination with tandem mass spectrometry. Rapid Commun Mass Spectrom 19:3322-3330

    PubMed  CAS  Google Scholar 

  • Yin W, Doss GA, Stearns RA, Chaudhary AG, Hop CE, Franklin RB, Kumar S (2003) A novel P450-catalyzed transformation of the 2,2,6,6-tetramethyl piperidine moiety to a 2,2-dimethyl pyrrolidine in human liver microsomes: characterization by high resolution quadrupole-time-of-flight mass spectrometry and 1H-NMR. Drug Metab Dispos 31:215-223

    PubMed  CAS  Google Scholar 

  • Yin W, Mitra K, Stearns RA, Baillie TA, Kumar S (2004) Conversion of the 2,2,6,6-tetramethylpiperidine moiety to a 2,2-dimethylpyrrolidine by cytochrome P450: evidence for a mechanism involving nitroxide radicals and heme iron. Biochemistry 43:5455-5466

    PubMed  CAS  Google Scholar 

  • Zhang F, Swanson SM, van Breemen RB, Liu X, Yang Y, Gu C, Bolton JL (2001) Equine estrogen metabolite 4-hydroxyequilenin induces DNA damage in the rat mammary tissues: formation of single-strand breaks, apurinic sites, stable adducts, and oxidized bases. Chem Res Toxicol 14:1654-1659

    PubMed  CAS  Google Scholar 

  • Zhang Z, Chen Q, Li Y, Doss GA, Dean BJ, Ngui JS, Silva EM, Kim S, Wu JY, Dininno F, Hammond ML, Stearns RA, Evans DC, Baillie TA, Tang W (2005) In vitro bioactivation of dihydrobenzoxathiin selective estrogen receptor modulators by cytochrome P450 3A4 in human liver microsomes: formation of reactive iminium and quinone type metabolites. Chem Res Toxicol 18:675-685

    PubMed  CAS  Google Scholar 

  • Zhou S, Chan E, Duan W, Huang M, Chen YZ (2005) Drug bioactivation, covalent binding to target proteins and toxicity relevance. Drug Metab Rev 37:41-213

    PubMed  CAS  Google Scholar 

  • Zhu M, Ma L, Zhang D, Ray K, Zhao W, Humphreys WG, Skiles G, Sanders M, Zhang H (2006) Detection and characterization of metabolites in biological matrices using mass defect filtering of liquid chromatography/high resolution mass spectrometry data. Drug Metab Dispos 34:1722-1733

    PubMed  CAS  Google Scholar 

  • Zhu M, Ma L, Zhang H, Humphreys WG (2007) Detection and structural characterization of glutathione-trapped reactive metabolites using liquid chromatography-high-resolution mass spectrometry and mass defect filtering. Anal Chem 79:8333-8341

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The authors would like to thank Drs. Alana Upthagrove and Timothy Schultz-Utermoehl for some of the studies discussed in this chapter.

Author information

Authors and Affiliations

  1. Department of Drug Metabolism and Pharmacokinetics, Merck Research Laboratories, Rahway, New Jersey, USA

    Sanjeev Kumar

Authors
  1. Sanjeev Kumar
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kaushik Mitra
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kelem Kassahun
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Thomas A. Baillie
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sanjeev Kumar .

Editor information

Editors and Affiliations

  1. Faculty of Pharmacy, University of Toronto, Toronto, Canada, M5S 2S2

    Jack Uetrecht (Professor of Pharmacy and Medicine, Canada Research Chair in Adverse Drug Reactions) (Professor of Pharmacy and Medicine, Canada Research Chair in Adverse Drug Reactions)

Rights and permissions

Reprints and permissions

Copyright information

© 2010 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Kumar, S., Mitra, K., Kassahun, K., Baillie, T.A. (2010). Approaches for Minimizing Metabolic Activation of New Drug Candidates in Drug Discovery. In: Uetrecht, J. (eds) Adverse Drug Reactions. Handbook of Experimental Pharmacology, vol 196. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-00663-0_19

Download citation

Publish with us

Policies and ethics

Search

Navigation