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Review Article

Metabolic bioactivation and drug-related adverse effects: current status and future directions from a pharmaceutical research perspective

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Pages 225-249 | Received 16 Jul 2009, Accepted 07 Oct 2009, Published online: 26 Nov 2009

References

  • Abboud, G., Kaplowitz, N. (2007). Drug-induced liver injury. Drug Saf 30:277–294.
  • Anders, M. W. (2005). Formation and toxicity of anesthetic degradation products. Annu Rev Pharmacol Toxicol 45:147–176.
  • Anders, M. W., Dekant, W. (1998). Glutathione-dependent bioactivation of haloalkenes. Annu Rev Pharmacol Toxicol 38:501–537.
  • AstraZeneca. (2006). Press release. Available at: www.astrazeneca.com/media/latest-press-releases/2006. (Accessed February 7, 2009).
  • Baer, B. R., Wienkers, L. C., Rock, D. A. (2007). Time-dependent inactivation of P450 3A4 by raloxifene: identification of Cys239 as the site of apoprotein alkylation. Chem Res Toxicol 20:954–964.
  • Baillie, T. A. (2008). Metabolism and toxicity of drugs. Two decades of progress in industrial drug metabolism. Cehm Res Toxicol 21:129–137.
  • Baillie, T. A., Slatter, J. G. (1991). Glutathione—a vehicle for the transport of chemically reactive metabolites. Acc Chem Res 24:264–270.
  • Batist, G., Ramakrishnan, G., Rao, C. S., Chandrasekharan, A., Gutheil, J., Guthrie, T., et al. (2001). Reduced cardiotoxicity and preserved antitumor efficacy of liposome-encapsulated doxorubicin and cyclophosphamide compared with conventional doxorubicin and cyclophosphamide in a randomized, multicenter trial of metastatic breast cancer. J Clin Oncol 19:1444–1454.
  • Baughman, T. M., Graham, R. A., Wells-Knecht, K., Silver, I. S., Tyler, L. O., Wells-Knecht, M., et al. (2005). Metabolic activation of pioglitazone identified from rat and human liver microsomes and freshly isolated hepatocytes. Drug Metab Dispos 33:733–738.
  • Bauman, J. N., Frederick, K. S., Sawant, A., Walsky, R. L., Cox, L. M., Obach, R. S., et al. (2008). Comparison of the bioactivation potential of the antidepressant and hepatotoxin nefazodone with aripiprazole, a structural analog and marketed drug. Drug Metab Dispos 36:1016–1029.
  • Beaune, P., Dansette, P. M., Mansuy, D., Kiffel, L., Finck, M., Amar, C., et al. (1987). Human anti-endoplasmic reticulum autoantibodies appearing in a drug-induced hepatitis are directed against a human liver cytochrome P-450 that hydroxylates the drug. Proc Natl Acad Sci U S A 84:551–555.
  • Benson, M. D., Aldo-Benson, M., Brandt, K. D. (1985). Synovial fluid concentrations of diclofenac in patients with rheumatoid arthritis or osteoarthritis. Semin Arthr Rheum 15:65–67.
  • Bhaskaran, K., Hamouda, O., Sannes, M., Boufassa, F., Johnson, A. M., Lambert, P. C., et al. (2008). Changes in the risk of death after HIV seroconversion compared with mortality in the general population. JAMA 300:51–59.
  • Blain, P. G., Battershill, J. M., Venitt, S., Copper, C. C., Fielder, R. J. (1998). Consideration of short-term carcinogenicity tests using transgenic mouse models. Mutat Res 403:259–263.
  • Boelisterli, U. A., Hsiao, C-J. J. (2008). The heterozygous Sod2+/- mouse: modeling the mitochondrial role in drug toxicity. Drug Discov Today 13:982–988.
  • Borzelleca, J. F. (2000). Paracelsus: herald of modern toxicology. Toxicol Sci 53:2–4.
  • Bourdi, M., Chen, W., Peter, R. M., Martin, J. L., Buters, J. T. M., Nelson, S. D., et al. (1996). Human cytochrome P450 2E1 is a major autoantigen associated with halothane hepatitis. Chem Res Toxicol 9:1159–1166.
  • Brinker, A. D., Wassel, R. T., Lyndly, J., Serrano, J., Avigan, M., Lee, W. M., et al. (2009). Telithromycin-associated hepatotoxicity: clinical spectrum and causality assessment of 42 cases. Hepatology 49:250–257.
  • Brune, K. (2007). Persistence of NSAIDs at effect sites and rapid disappearance from side-effect compartments contributes to tolerability. Curr Med Res Opin 23:2985–2995.
  • Caraco, Y., Blotnick, S., Muszkat, M. (2008). CYP2C9 genotype-guided warfarin prescribing enhances the efficacy and safety of anticoagulation: a prospective, randomized, controlled study. Clin Pharmacol Ther 83:460–470.
  • Carlson, T. J., Fisher, M. B. (2008). Recent advances in high-throughput screening for ADME properties. Comb Chem High Throughput Screen 11:258–264.
  • Chalasani, N., Fontana, R. J., Bonkovsky, H. L., Watkins, P. B., Davern, T., Serrano, J., et al. (2008). Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Gastroenterology 135:1924–1934.
  • Chen, C., Krausz, K. W., Shah, Y. M., Idle, J. R., Gonzalez, F. J. (2009). Serum metabolomics reveals irreversible inhibition of fatty acid β-oxidation through the suppression of PPARα activation as a contributing mechanism of acetaminophen-induced hepatotoxicity. Chem Res Toxicol 22:699–707.
  • Chen, Q., Doss, G. A., Tung, E. C., Liu, W., Tang, Y. S., Braun, M. P., et al. (2006). Evidence for the bioactivation of zomepirac and tolmetin by an oxidative pathway: identification of glutathione adducts in vitro in human liver microsomes and in vivo in rats. Drug Metab Dispos 34:145–151.
  • Chen, Q., Ngui, J. S., Doss, G. A., Wang, R. W., Cai, X., DiNinno, F. P., et al. (2002). Cytochrome P450 3A4-mediated bioactivation of raloxifene: irreversible enzyme inhibition and thiol adduct formation. Chem Res Toxicol 15:907–914.
  • Chen, W., Shockcor, J. P., Tonge, R., Hunter, A., Gartner, C., Nelson, S. D. (1999). Protein and nonprotein cysteinyl thiol modification by N-acetyl-p-benzoquinone imine via a novel ipso adduct. Biochemistry 38:8159–8166.
  • Clayton, T. A., Lindon, J. C., Cloarec, O., Antti, H., Charuel, C., Hanton, G., et al. (2006). Pharmaco-metabonomic phenotyping and personalized drug treatment. Nature 440:1073–1077.
  • Clercq, E. D. (2009). Anti-HIV drugs: 25 compounds approvde within 25 years after the discovery of HIV. Int J Antimicrob Agents 33:307–320.
  • Colacino, J. M. (1996). Mechanism for the anti-hepatitis B virus activity and mitochondrial toxicity if fialuridine (FIAU). Antiviral Res 29:125–139.
  • Cote, J-F., Kirzin, S., Kramar, A., Mosnier, J-F., Diebold, M-D., Soubeyran, I., et al. (2007). UGT1A1 polymorphism can predict hematologic toxicity in patients treated with irinotecan. Clin Cancer Res 13:3269–3275.
  • Cullen, J. M., Miller, R. T. (2006). The role of pathology in the identification of drug-induced hepatic toxicity. Exp Opin Drug Metab Toxicol 2:241–247.
  • Day, R. O., McLachlan, A. J., Graham, G. G., Williams, K. M. (1999). Pharmacokinetics of nonsteroidal anti-inflammatory drugs in synovial fluid. Clin Pharmacokinet 36:191–210.
  • Day, S. H., Mao, A., White, R., Schulz-Utermoehl, T., Miller, R., Beconi, M. G. (2005). A semi-automated method for measuring the potential for protein covalent binding in drug discovery. J Pharmacol Toxicol Meth 52:278–285.
  • de Leon, J., Susce, M. T., Murray-Carmichael, E. (2006). The AmpliChip™ CYP450 genotyping test: integrating a new clinical tool. Mol Diagn Ther 10:135–151.
  • Debbage, P. (2009). Targeted drugs and nanomedicine: present and future. Curr Pharm Des 15:153–172.
  • Degoul, F., Sutton, A., Mansouri, A., Cepanec, C., Degott, C., Fromenty, B., et al. (2001). Homozygosity for alanine in the mitochondrial targeting sequence of superoxide dismutase and risk for severe alcohol liver disease. Gastroenterology 120:1468–1474.
  • DeLeve, L. D., Kaplowitz, N. (1991). Glutathione metabolism and its role in hepatotoxicity. Pharm Ther 52:287–305.
  • DeSanty, K. P., Amabile, C. M. (2007). Antidepressant-induced liver injury. Ann Pharmacother 41:1201–1211.
  • Dieckhaus, C. M., Fernandez-Metzler, C. L., King, R., Krolikowski, P. H., Baillie, T. A. (2005). Negative ion tandem mass spectrometry for the detection of glutathione conjugates. Chem Res Toxicol 18:630–638.
  • Drummond, D. C., Meyer, O., Hong, K., Kirpotin, D. B., Papahadjopoulos, D. (1999). Optimizing liposomes for delivery of chemotherapeutic agents to solid tumors. Pharmacol Rev 51:691–743.
  • Dykens, J. A., Jamieson, J. D., Marroquin, L. D., Nadanaciva, S., Xu, J. J., Dunn, M. C., et al. (2008). In vitro assessment of mitochondrial dysfunction and cytotoxicity of nefazodone, trazodone, and buspirone. Toxicol Sci 103:335–345.
  • Eastin, W. C., Haseman, J. K., Mahler, J. F., Bucher, J. R. (1998). Testing compounds in genetically altered mice. Toxicol Pathol 26:461–473.
  • Erives, G. V., Lau, S. S., Monks, T. J. (2008). Accumulation of neurotoxic thioether metabolites of 3,4-(±)-methylenedioxymethamphetamine in rat brain. J Pharmacol Exp Ther 324:284–292.
  • Evans, D. C., Watt, A. P., Nicoll-Griffith, D. A., Baillie, T. A. (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.
  • Evista®. Prescribing information. (2008) Available at: www.evista.com. (Accessed January 10, 2009).
  • Fernandes, N, Geller, S. A., Fong, T-L. (1998). Terbinafine hepatotoxicity: case report and review of the literature. Am J Gastroenterol 93:459–460.
  • Fernandes, N. F., Martin, R. R., Schenker, S. (2000). Trazodone-induced hepatotoxicity: a case report with comments on drug-induced hepatotoxicity. Am J Gastroenterol 95:532–535.
  • FDA. (2009). Tables of valid genomic biomarkers in the context of approved drug labels. Available at: www.fda.gov/Drugs/ScienceResearch/ResearchAreas/Pharmacogenetics/default.htm. (Accessed January 17, 2009).
  • Funk, C., Pantze, M., Jehle, L., Ponelle, C., Scheuermann, G., Lazendic, M., et al. (2001a). Troglitazone-induced intrahepatic cholestasis by an interference with the hepatobiliary export of bile acids in male and female rats: correlation with the gender difference in troglitazone sulfate formation and the inhibition of the canalicular bile salt export pump (BSEP) by troglitazone and troglitazone sulfate. Toxicology 167:83–98.
  • Funk, C., Ponelle, C., Scheuermann, G., Pantze, M. (2001b). Cholestatic potential of troglitazone as a possible factor contributing to troglitazone-induced hepatotoxicity: in vivo and in vitro interaction at the canalicular bile salt export pump (BSEP) in the rat. Mol Pharmacol 59:627–635.
  • Gan, J., Ruan, Q., He, B., Zhu, M., Shyu, W. C., Humphreys, W. G. (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 22:690–698.
  • Ghanbari, F., Rowland-Yeo, K., Bloomer, J. C., Clarke, S. E., Lennard, M. S., Tucker, G. T., et al. (2006). A critical evaluation of the experimental design of studies of mechanism based enzyme inhibition, with implications for in vitro–in vivo extrapolation. Curr Drug Metab 7:315–334.
  • Glatt, H. (1997). Bioactivation of mutagens via sulfation. FASEB J 11:314–321.
  • Greaves, P., Williams, A., Eve, M. (2004). First dose of potential new medicines to humans: how animals help. Nat Rev Drug Discov 3:226–236.
  • Greene, D. S., Barbhaiya, R. H. (1997). Clinical pharmacokinetics of nefazodone. Clin Pharmacokinet 33:260–275.
  • Guengerich, F. P., MacDonald, T. L. (1990). Mechanism of cytochrome P-450 catalysis. FASEB J 4:2453–2459.
  • Hagmann, W. K. (2008). The discovery of taranabant, a selective cannabinoid-1 receptor inverse agonist for the treatment of obesity. Arch Pharm Chem Life Sci 341:405–411.
  • Hanna, P. E. (1996). Metabolic activation and detoxification of arylamines. Curr Med Chem 3:195–210.
  • Hargus, S. J., Martin, B. M., George, J. W., Pohl, L. R. (1995). Covalent modification of rat liver dipeptidyl peptidase IV (CD26) by the nonsteroidal anti-inflammatory drug, diclofenac. Chem Res Toxicol 8:993–996.
  • He, K., Woolf, T. F., Hollenberg, P. F. (1999). Mechanism-based inactivation of cytochrome P-450-3A4 by mifepristone (RU486). J Pharmacol Exp Ther 288:791–797.
  • Herceptin. Package insert. (2003) Available at: www.genentechaccesssolutions.com/herceptin/professional/forms/PI.jsp. (Accessed February 7, 2009).
  • Hinson, J. A., Reid, A. B., McCullough S. S., James, L. P. (2004). Acetaminophen-induced hepatotoxicity: role of metabolic activation, reactive oxygen/nitrogen species, and mitochondrial permeability transition. Drug Metab Rev 36:805–822.
  • Hinz, B., Brune, K. (2008). Can drug removals involving cyclooxygenase-2 inhibitors be avoided? A plea for human pharmacology. Trends Pharmacol Sci 29:391–397.
  • Honma, W., Shimada, M., Sasano, H., Ozawa, S., Miyata, M., Nagata, K., et al. (2002). Phenol sulfotransferase, ST1A3, as the main enzyme catalyzing sulfation of troglitazone in human liver. Drug Metab Dispos 30:944–949.
  • Huang, Y-S., Su, W-J., Huang, Y-H., Chen, C-Y., Chang, F-Y., Lin, H-C., et al. (2007). Genetic polymorphisms of manganese superoxide dismutase, NAD(P)H:quinone oxidoreductase, glutathione S-transferase M1 and T1, and the susceptibility to drug-induced liver injury. J Hepatol 47:128–134.
  • Ito, K., Ogihara, K., Kanamitsu, S-I., Itoh, T. (2003). Prediction of the in vivo interaction between midazolam and macrolides based on in vitro studies using human liver microsomes. Drug Metab Dispos 31:945–954.
  • Iverson, S. L., Uetrecht, J. P. (2001). Identification of a reactive metabolite of terbinafine: insights into terbinafine-induced hepatotoxicity. Chem Res Toxicol 14:175–181.
  • Jaeschke, H. (2005). Role of inflammation in the mechanism of acetaminophen-induced hepatotoxicity. Exp Opin. Drug Metab Toxicol 1:389–397.
  • Jaeschke, H., Bajt M. L. (2006). Intracellular signaling mechanisms of acetaminophen-induced liver cell death. Toxicol Sci 89:31–41.
  • Jaeschke, H., Gores, G. J., Cederbaum, A. I., Hinson, J. A., Pessayre, D., Lemasters, J. J. (2002). Mechanisms of hepatotoxicity. Toxicol Sci 65:166–176.
  • James, L. P., Capparelli, E. V., Simpson, P. M., Letzig, L., Roberts, D., Hinson, J. A., et al. (2008). Acetaminophen-associated hepatic injury: evaluation of acetaminophen protein adducts in children and adolescents with acetaminophen overdose. Clin Pharmacol Ther 84:684–690.
  • Jones, A. F., Vale, J. A. (1993). Paracetamol poisoning and the kidney. J Clin Pharm Ther 18:5–8.
  • Jones, D. C., Duvauchelle, C. D., Ikegami, A., Olsen, C. M., Lau, S. S., de la Torre, R. et, al. (2005). Serotonergic neurotoxic metabolites of ecstasy identified in rat brain. J Pharmacol Exp Ther 313:422–431.
  • Kaitin, K. I. (2008). Obstacles and opportunities in new drug development. Clin Pharmacol Ther 83:210–212.
  • Kalgutkar, A. S., Soglia, J. R. (2005). Minimizing the potential for metabolic activation in drug discovery. Exp Opin Drug Metab Toxicol 1:91–142.
  • Kalgutkar, A. S., Vaz, A. D. N., Lame, M. E., Henne, K. R., Soglia, J., Zhao, S. X., et al. (2005). Bioactivation of the nontricyclic antidepressant nefazodone to a reactive quinone-imine species in human liver microsomes and recombinant cytochrome P450 3A4. Drug Metab Dispos 33:243–253.
  • Kashimshetty, R., Desai, V. G., Kale, V. M., Lee, T., Moland, C. L., Branham, W. S., et al. (2009). Underlying mitochondrial dysfunction triggers flutamide-induced oxidative liver injury in a mouse model of idiosyncratic drug toxicity. Toxicol Appl Pharmcol 238:150–159.
  • Kassahun, K., Hu, P., Grillo, M. P., Davis, M. R., Jin, L., Baillie, T. A. (1994). Metabolic activation of unsaturated derivatives of valproic acid: identification of novel glutathione adducts formed through coenzyme A-dependent and -independent processes. Chem Biol Interact 90:253–275.
  • Kassahun, K., Pearson, P. G., Tang, W., McIntosh, I., Leung, K., Elmore, C., et al. (2001). Studies on the metabolism of troglitazone to reactive intermediates in vitro and in vivo: evidence for novel bioactivation pathways involving quinone methide formation and thiazolidinedione ring scission. Chem Res Toxicol 14:62–70.
  • Kenne, K., Skanberg, I., Glinghammar, B., Berson, A., Pessayre, D., Flinois, J-P., et al. (2008). Prediction of drug-induced liver injury in humans by using in vitro methods: the case of ximelagatran. Toxicol In Vitro 22:730–746.
  • Ketterer, B., Mulder, G. (1990). Glutathione conjugation. In:Mulder, G. J. (Ed.), Conjugation reaction in drug metabolism (pp 307–364). New York: Taylor & Francis.
  • Khan, K. K., He, Y. Q., Correia, M. A., Halpert, J. R. (2002). Differential oxidation of mifepristone by cytochromes P450 3A4 and 3A5: selective inactivation of P450 3A4. Drug Metab Dispos 30:985–990.
  • Kleiner, D. E., Gaffey, M. J., Sallie, R., Tsokos, M., Nichols, L., McKenzie, R., et al. (1997). Histopathology changes associated with fialuridine hepatotoxicity. Mod Pathol 10:192–199.
  • Kumar, S., Kassahun, K., Tschirret-Guth, R. A., Mitra, K., Baillie, T. A. (2008). Minimizing metabolic activation during pharmaceutical lead optimization: progress, knowledge gaps, and future directions. Curr Opin Drug Discov Dev 11:43–52.
  • Kola, I. (2008). The state of innovation in drug development. Clin Pharmacol Ther 83:227–230.
  • Kostrubsky, S. E., Strom, S. C., Kalgutkar, A. S., Kulkarni, S., Atherton, J., Mireles, R., et al. (2006). Inhibition of hepatobiliary transport as a predictive method for clinical hepatotoxicity of nefazodone. Toxicol Sci 90:451–459.
  • Labbe, G., Pessayre, D., Fromenty, B. (2008). Drug-induced liver injury through mitochondrial dysfunction: mechanisms and detection during preclinical safety studies. Fund Clin Pharmacol 22:335–353.
  • Lewis, W., Griniuviene, B., Tankersley, K. O., levine, E. S., Montione, R., Engelman, L., et al. (1997). Depletion of mitochondrial DNA, destruction of mitochondria, and accumulation of lipid droplets result from fialuridine treatment in woodchucks (Marmota monax). Lab Invest 76:77–87.
  • Li, C., Olurinde, M. O., Hodges, L. M., Grillo M. P., Benet, L. Z. (2003). Covalent binding of 2-phenylpropionyl-S-acyl-CoA thioester to tissue proteins in vitro. Drug Metab Dispos 31:727–730.
  • Lim, H. K., Chen, J., Cook, K., Sensenhauser, C., Silva, J., Evans, D. C. (2008). A generic method to detect electrophilic intermediates using isotopic pattern triggered data-dependent high-resolution accurate mass spectrometry. Rapid Commun Mass Spectrom 22:1295–1311.
  • Lin, J. H. (1999). Role of pharmacokinetics in the discovery and development of indinavir. Adv Drug Deliv Rev 39:33–49.
  • Link, E., Parish, S., Armitage, J., Bowman, L., Heath, S., Matsuda, F., et al. (2008). SLCO1B1 variants and statin-induced myopathy—a genomewide study. NEJM 359:789–799.
  • Liu, X., Chen, C., Smith, B. J. (2008). Progress in brain penetration evaluation in drug discovery and development. J Pharmacol Exp Ther 325:349–356.
  • Liu, Z-X., Kaplowitz, N. (2006). Role of innate immunity in acetaminophen-induced hepatotoxicity. Exp Opin Drug Metab Toxicol 2:493–503.
  • Lucena, M. I., Carvajal, A., Andrade, R. J., Velasco, A. (2003). Antidepressant-induced hepatotoxicity. Exp Opin Drug Saf 2:249–262.
  • Madan, A., Usuki, E., Burton, A., Ogilvie, B. W., Parkinson, A. (2002). In vitro approaches for studying the inhibition of drug-metabolizing enzymes and identifying the drug-metabolizing enzymes responsible for the metabolism of drugs. In:Rodrigues, A. D. (Ed.), Drug-drug interactions (pp 217–294). New York: Marcel Dekker.
  • Mallat, A., Zafrani, E. S., Metreau, J. M., Dhumeaux, D. (1997). Terbinafine-induced prolonged cholestasis with reduction of interlobular bile ducts. Digest Dis Sci 42:1486–1488.
  • Mallikaarjun, S., Salazar, D. E., Bramer, S. L. (2004). Pharmacokinetics, tolerability, and safety of aripiprazole following multiple oral dosing in normal healthy volunteers. J Clin Pharmacol 44:179–187.
  • Manyike, P. T., Kharasch, E. D., Kalhorn, T. F., Slattery, J. T. (2000). Contribution of CYP2E1 and CYP3A to acetaminophen reactive metabolite formation. Clin Pharmacol Ther 67:275–282.
  • Martin, J. L., Plevak, D. J., Flannery, K. D., Charlton, M., Poterucha, J. J., Humphreys, C. E., et al. (1995). Hepatotoxicity after desflurane anesthesia. Anesthesiology 83:1125–1129.
  • Masubuchi, Y. (2006). Metabolic and non-metabolic factors determining troglitazone hepatotoxicity: a review. Drug Metab Pharmacokinet 21:347–356.
  • McKenzie, R., Fried M. W., Sallie, R., Conjeevaram, H., DiBisceglie, A. M., Park, Y., et al. (1995). Hepatic failure and lactic acidosis due to fialuridine (FIAU), an investigational nucleoside analogue for chronic hepatitis B. NEJM 333:1099–1105.
  • Mitchell, P. S., Parkin, R. K., Kroh, E. M., Fritz, B. R., Wyman, S. K., Pogosova-Agadjanyan, E. L., et al. (2008b). Circulating microRNAs as stable blood-based markers for cancer detection. Proc Natl Acad Sci U S A 105:10513–10518.
  • Mitchell, M. D., Elrick, M. M., Walgren, J. L., Mueller, R. A., Morris, D. L., Thompson, D. C. (2008a). Peptide-based in vitro assay for the detection of reactive metabolites. Chem Res Toxicol 21:859–868.
  • Monks, T. J., Lau, S. S. (1994). Glutathione conjugation as a mechanism for the transport of reactive metabolites. Adv Pharmacol 27:183–210.
  • Monks, T. J, Lau, S. S. (1998). The pharmacology and toxicology of polyphenolic-glutathione conjugates. Annu Rev Pharmacol Toxicol 38:229–255.
  • Mortishire-Smith, R. J., Skiles, G. L., Lawrence, J. W., Spence, S., Nicholls, A. W., Johnson, B. A., et al. (2004). Use of metabonomics to identify impaired fatty acid metabolism as the mechanism of a drug-induced toxicity. Chem Res Toxicol 17:165–173.
  • Muldrew, K. L., James, L. P., Coop, L., McCullough, S. S., Hendrickson, H. P., Hinson, J. A., et al. (2002). Determination of acetaminophen-protein adducts in mouse liver and serum and human serum after hepatotoxic doses of acetaminophen using high-performance liquid chromatography with electrochemical detection. Drug Metab Dispos 30:446–451.
  • Mullin, R. (2003). Drug development costs about $1.7 billion. Chem Eng News 81:8.
  • Myers, T. G., Dietz, E. C., Anderson, N. L, Khairallah, E. A., Cohen, S. D., Nelson, S. D. (1995). A comparative study of mouse liver protein arylated by reactive metabolites of acetaminophen and its nonhepatotoxic regioisomer, 3’-hydroxyacetanilide. Chem Res Toxicol 8:403–413.
  • Nakayama, S., Atsumi, R., Takakusa, H., Kobayashi, Y., Kurihara, A., Nagai, Y., et al. (2009). A zone clarification system for risk assessment of idiosyncratic toxicity using daily dose and covalent binding. Drug Metab Dispos 37:1970–1977.
  • Neuberger, J. M. (1990). Halothane and hepatitis: incidence, predisposing factors, and exposure guidelines. Drug Saf 5:28–38.
  • Niemi, M., Schaeffeler, E., Lang, T., Fromm, M. F., Neuvonen, M., Kyrklund, C., et al. (2004). High plasma pravastatin concentrations are associated with single nucleotide polymorphisms and haplotypes of organic anion transporting polypeptide-C (OATP-C, SLCO1B1). Pharmacogenetics 14:429–440.
  • Njoku, D., Laster, M. J., Gong, D. H., Eger II, E. I., Reed, G. F., Martin, J. L. (1997). Biotransformation of halothane, enflurane, isoflurane, and desflurane to trifluoroacetylated liver proteins: association between protein acylation and hepatic injury. Anesth Analg 84:173–178.
  • Obach, R. S., Kalgutkar, A. S., Soglia, J. R., Zhao, S. X. (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 21:1814–1822.
  • Olson, H., Betton, G., Robinson, D., Thomas, K., Monro, A., Kolaja, G., et al. (2000). Concordance of the toxicity of pharmaceuticals in humans and in animals. Regul Toxicol Pharmacol 32:56–67.
  • Ong, M. M. K., Latchoumycandane, C., Boelsterli, U. A. (2006). Troglitazone-induced hepatic necrosis in an animal model of silent genetic mitochondrial abnormalities. Toxicol Sci 97:205–213.
  • Oritiz de Montellano, P. R. (1989). Cytochrome P450 catalysis: radical intemediates and dehydrogenation reactions. Trends Pharmacol Sci 10:354–359.
  • Overdevest, J. B., Theodorescu, D., Lee, J. K. (2009). Utilizing the molecular gateway: the path to personalized cancer management. Clin Chem 55:684–697.
  • Palovaara, S., Kivisto, K. T., Tapanainen, P., Manninen, P., Neuvonen, P., Laine, K. (2000). Effect of an oral contraceptive preparation containing ethinylestradiol and gestodene on CYP3A4 activity as measured by midazolam 1’-hydroxylation. Clin Pharmacol 50:333–337.
  • Pasanen, M. K., Neuvonen, M., Neuvonen, P. J., Niemi, M. (2006). SLCO1B1 plotmorphism markedly affects the pharmacokinetics of simvastatin acid. Pharmacogenet Genom 16:873–879.
  • Pohl, L. R. (1990). Drug-induced allergic hepatitis. Semin Liver Dis 10:305–315.
  • Pohl, L. R., Branchflower, R. V. (1981). Covalent binding of electrofilic metabolites to macromolecules. Meth Enzymol 77:43–50.
  • Polasek, T. M., Miners, J. O. (2006). Quantitative prediction of macrolide drug-drug interaction potential from in vitro studies using testosterone as the human cytochrome P4503A substrate. Pharmacokint Dispos 62:203–208.
  • Ponchaut, S., van Hoof, F., Veitch, K. (1992). In vitro effects of valproate and valproate metabolites on mitochondrial oxidations: relevance of CoA sequestration to the observed inhibitions. Biochem Pharmacol 43:2435–2442.
  • Prakash, C., Sharma, R., Gleave, M., Nedderman, A. (2008). In vitro screening techniques for reactive metabolites for minimizing bioactivation potential in drug discovery. Curr Drug Metab 9:952–964.
  • Rashed, M. S., Myers, T. G., Nelson, S. D. (1990). Hepatic protein arylation, glutathione depletion, and metabolites profiles of acetaminophen and a non-hepatotoxic regioisomer, 3’-hydroxyacetanilide, in the mouse. Drug Metab Dispos 18:765–770.
  • Raskind, J. Y., El-Chaar, G. M. (2000). The role of carnitine supplementation during valproic acid therapy. Ann Pharmacother 34:630–638.
  • Rieder, M. J. (2009). Immune mediation of hypersensitivity adverse drug reactions: implications for therapy. Exp Opin Drug Saf 8:331–343.
  • Rodrigues, A. D., Winchell, G. A., Dobrinska, M. R. (2001). Use of in vitro drug metabolism data to evaluate metabolic drug-drug interactions in man: the need for quantitative databases. J Clin Pharmacol 41:368–373.
  • Roth, R. A., Luyendyk, J. P., Maddox, J. F., Ganey, P. E. (2003). Inflammation and drug idiosyncrasy—is there a connection? J Pharmacol Exp Ther 307:1–8.
  • Ruepp, S. U., Tonge, R. P., Shaw, J., Wallis, N., Pognan, F. (2002). Genomics and proteomics analysis of acetaminophen toxicity in mouse liver. Toxicol Sci 65:135–150.
  • Samuel, K., Yin, W., Stearns, R. A., Tang, Y. S., Chaudhary, A. G., Jewell, J. P., et al. (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.
  • Sanderson, J. P., Naisbitt, D. J., Park, B. K. (2006). Role of bioactivation in drug-induced hypersensitivity reactions. AAPS J 8:E55–E64.
  • Scatena, R., Bottoni, P., Botta, G., Martorana, G. E., Giardina, B. (2007). The role of mitochondria in pharmacotoxicology: a reevaluation of an old, newly emerging topic. Am J Physiol Cell Physiol 293:C12–C21.
  • Shakeri-Nejad, K., Stahlmann, R. (2006). Drug interactions during therapy with three major groups of antimicrobial agents. Exp Opin Pharmacother 7:639–651.
  • Shenton, J. M., Popovic, M., Chen, J., Masson, M. J., Uetrecht, J. P. (2005). Evidence of an immune-mediated mechanism for an idiosyncratic nevirapine-induced reaction in the female brown Norway rat. Chem Res Toxicol 18:1799–1813.
  • Silva, M. F. B., Ijst, L., Allers, P., Jakobs, C., Duran, M., de Almeida, I. T., et al. (2004). Valproyl-dephosphoCoA: a novel metabolite of valproate formed in vitro in rat liver mitochondria. Drug Metab Dispos 32:1304–1310.
  • Slamon, D. J., Clark, G. M., Wong, S. G., Levin, W. J., Ullrich, A., McGuire, W. L. (1987). Human breast cancer: correlation of relapse and survival with amplification of the HER2-2/neu oncogene. Science 235:177–182.
  • Slamon, D. J., Leyland-Jones, B., Shak, S., Fuchs, H., Paton, V., Bajamonde, A., et al. (2001). Use of chemotherapy plus a monoclonal antibody against Hers for metastatic breast cancer that overexpresses Hers. NEJM 344:783–792.
  • Slavin, D. E., Schlichting, C. L., Freston, J. W. (2005). Rating the severity of the medical consequences of drug-induced liver injury. Regul Toxicol Pharmacol 43:134–140.
  • Smith, M. T. (2003). Mechanisms of troglitazone hepatotoxicity. Chem Res Toxicol 16:679–687.
  • Somchit, N., Wade, L. T., Ramsay, L., Goldin, R. D., Kenna, J. G., Caldwell, J. (1997). Hepatotoxicity and hepatic protein adduct formation in rats dosed i.p. with diclofenac. Hum Exp Toxicol 16:401.
  • Spahn-Langguth, H., Benet L. Z. (1992). Acyl glucuronides revisited: is the glucuronidation process a toxification as well as detoxification mechanism? Drug Metab Rev 24:5–48.
  • Stern, S. T., Bruno, M. K., Hennig, G. E., Horton, R. A., Roberts, J. C., Cohen, S. D. (2005a). Contribution of acetaminophen-cysteine to acetaminophen nephrotoxicity in CD-1 mice: I. Enhancement of acetaminophen nephrotoxicity by acetaminophen-cysteine. Toxicol Appl Pharmacol 202:151–159.
  • Stern, S. T., Bruno, M. K., Horton, R. A., Hill, D. W., Roberts, J. C., Cohen, S. D. (2005b). Contribution of acetaminophen-cysteine to acetaminophen nephrotoxicity in CD-1 mice: II. Possible involvement of the γ-glutamyl cycle. Toxicol Appl Pharmacol 202:160–171.
  • Summa, V., Petrocchi, A., Bonelli, F., Crescenzi, B., Donghi, M., Ferrara, M, et al. (2008). Discovery of raltegravir, a potent, selective orally bioavailable HIV-integrase inhibitor for the treatment of HIV-aids infection. J Med Chem 51:5843–5855.
  • Sun, J., Schnackenberg, L. K., Holland, R. D., Schmitt, T. C., Cantor, G. H., Dragan, Y. P., et al. (2008). Metabonomics evaluation of urine from rats given acute and chronic doses of acetaminophen using NMR and UPLC/MS. J Chromatogr B 871:328–340.
  • Takakusa, H., Masumoto, H., Yukinaga, H., Makino, C., Nakayama, S., Okazaki, O., et al. (2008). Covalent binding and tissue distribution/retention assessment of drugs associated with idiosyncratic drug toxicity. Drug Metab Dispos 36:1770–1779.
  • Tang, W. (2003). The metabolism of diclofenac—enzymology and toxicology perspectives. Curr Drug Metab 4:319–329.
  • Tang, W. (2007). Drug metabolite profiling and elucidation of drug-induced hepatotoxicity. Exp Opin Drug Metab Toxicol 3:407–420.
  • Tang, W., Abbott, F. S. (1996). Bioactivation of a toxic metabolite of valproic acid, (E)-2-propyl-2,4-pentadienoic acid, via glucuronidation: LC/MS/MS characterization of the GSH-glucuronide di-conjugates. Chem Res Toxicol 9:517–526.
  • Tang, W., Borel, A. G., Abbott, F. S. (1996). Conjugation of glutathione with a toxic metabolite of valproic acid, (E)-2-propyl-2,4-pentadienoic acid, catalyzed by rat hepatic glutathione S-transferases. Drug Metab Dispos 24:436–446.
  • Tang, W., Lu, A. Y. H. (2009). Drug metabolism and pharmacokinetics in support of drug design. Curr Pharm Des 15:2170–2183.
  • Tang, W., Stearns, R. A., Wang, R. W., Miller, R. R., Chen, Q., Ngui, J., et al. (2008). Assessing and minimizing time-dependent inhibition of cytochrome P450 3A in drug discovery: a case study with melanocortin-4 receptor agonists. Xenobiotica 38:1437–1457.
  • Tennant, B. C., Baldwin, B. H., Graham, L. A., Ascenzi, M. A., Hornbuckle, W. E., Rowland, P. H., et al. (1998). Antiviral activity and toxicity of fialuridine in the woodchuck model of hepatitis B virus infection. Hepatology 28:179–191.
  • Tirmenstein, M. A., Nelson, S. D. (1989). Subcellular binding and effects on calcium homeostasis produced by acetaminophen and a nonhepatotoxic regioisomer, 3’-hydroxyacetanilide, in mouse liver. J Biol Chem 264:9814–9819.
  • Tong, V., Teng, X. W., Chang, T. K. H., Abbott, F. S. (2005). Valproic acid II: effects on oxidative stress, mitochondrial membrane potential, and cytotoxicity in glutathione-depleted rat hepatocytes. Toxicol Sci 86:436–443.
  • Townsend, D. M., Hanigan, M. H. (2002). Inhibition of γ-glutamyl transpeptidase or cysteine S-conjugate β-lyase activity blocks the nephrotoxicity of cisplatin in mice. J Pharmacol Exp Ther 300:142–148.
  • Townsend, D. M., Tew, K. D., He, L., King, J. B., Hanigan, M. H. (2009). Role of glutathione S-transferase Pi in cisplatin-induced nephrotoxicity. Biomed Pharmacother 63:79–85.
  • Uetrecht, J. (1999). New concepts in immunology relevant to idiosyncratic drug reactions: the “danger hypothesis” and innate immune system. Chem Res Toxicol 12:387–395.
  • Uetrecht, J. (2006). Evaluation of which reactive metabolite, if any, is responsible for a specific idiosyncratic reaction. Drug Metab Rev 38:745–753.
  • Uetrecht, J. (2009). Immune-mediated adverse drug reactions. Chem Res Toxicol 22:24–34.
  • Umrethia, M., Ghosh, P., Majithya, R., Murthy, R. (2007). 6-mercaptopurine (6-MP) entrapped stealth liposomes for improvement of leukemic treatment without hepatotoxicity and nephrotoxicity. Cancer Invest 25:117–123.
  • Venkatakrishnan, K., Obach, R. S. (2007). Drug-drug interaction via mechanism-based cytochrome P450 inactivation: points to consider for risk assessment from in vitro data and clinical pharmacologic evaluation. Curr Drug Metab 8:449–462.
  • Waley, S. G. (1985). Kinetics of suicide substrates: practical procedures for determining parameters. Biochem J 227:843–849.
  • Wang, K., Zhang, S., Marzolf, B., Troisch, P., Brightman, A., Hu, Z., et al. (2009). Circulating microRNAs, potential biomarkers for drug-induced liver injury. Proc Natl Acad Sci U S A 106:4402–4407.
  • Watkins, P. B., Wrighton, S. A., Schuetz, E. G., Maurel, P., Guzelian, P. S. (1986). Macrolide antibiotics inhibit the degradation of the glucocorticoid-responsive cytochrome P-450p in rat hepatocytes in vivo and in primary monolayer culture. J Biol Chem 261:6264–6271.
  • Westphal, J. F. (2000). Macrolide-induced clinically relevant drug interactions with cytochrome P450 (CYP) 3A4: an update focused on clarithromycin, azithromycin, and dirithromycin. Br J Clin Pharmacol 50:285–295.
  • Wen, B., Ma, L., Rodrigues, D., Zhu, M. (2008a). Detection of novel reactive metabolites of trazodone: evidence for CYP2D6-mediated bioactivation of m-chlorophenylpiperazine. Drug Metab Dispos 36:841–850.
  • Wen, B., Ma, L., S. D. Nelson, S.D., Zhu, M. (2008b). High-throughput screening and characterization of reactive metabolites using polarity switching of hybrid triple quadrupole linear ion trap mass spectrometry. Anal Chem 80:1788–1799.
  • Williams, D. P. (2006). Toxicophores: investigations in drug safety. Toxicology 226:1–11.
  • Yamamoto, Y., Nakajima, M., Yamazaki, H., Yokoi, T. (2001). Cytotoxicity and apoptosis produced by troglitazone in human hepatoma cells. Life Sci 70:471–482.
  • Yamazaki, H., Shibata, A., Suzuki, M., Nakajima, M., Shimada, N., Guengerich, F. P., et al. (1999). Oxidation of troglitazone to a quinone-type metabolite catalyzed by cytochrome P-450 2C8 and P-450 3A4 in human liver microsomes. Drug Metab Dispos 27:1260–1266.
  • Yuan, L., Kaplowitz, N. (2009). Glutathione in liver disease and hepatotoxicity. Mol Asp Med 30:29–41.
  • Zhang, Z., Chen, Q., Li, Y., Doss, G. A., Dean, B. J., Ngui, J. S., et al. (2005). In vitro bioactivation of dihydrobenzoxathiin selective estrogen receptor modulators by cytochrome P450 3A4 in human liver microsomes: formation of reactive iminium and quinine-type metabolites. Chem Res Toxicol 18:675–685.
  • Zhang, Z., Gan, J. (2007). Protocols for assessment of in vitro and in vivo bioactivation potential of drug candidates. In:Zhang, D., Zhu, M., Humphreys, W. G. (Eds.), Drug metabolism in drug design and development: basic concepts and practice (pp 447–476). Hoboken, New Jersey, USA: John Wiley & Sons.
  • Zhang, Z., Zhu, M., Tang, W. (2009). Metabolite identification and profiling in drug design: current practice and future directions. Curr Pharm Des 15:2220–2235.
  • Zuckermann, J. M. (2004). Macrolides and ketolides: azithromycin, clarithromycin, telithromycin. Infect Dis Clin N Am 18:621–649.

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