Animal models of idiosyncratic drug reactions

Shenton, Jacintha; Chen, Jie; Uetrecht, Jack

doi:10.1016/j.cbi.2004.09.001

Cited by 90 publications

(78 citation statements)

References 79 publications

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“…IADRs are severe but so rare that they often are detected only after a large patient population has been exposed to the drug. This problem is further complicated by the limited value of preclinical safety models (Shenton et al, 2004). Biotransformation pathways leading to reactive metabolites have been documented via metabolite identification and chemical trapping studies (Kalgutkar and Soglia, 2005).…”

Section: Introductionmentioning

confidence: 99%

Bioactivation Pathways of the Cannabinoid Receptor 1 Antagonist Rimonabant

Bergström¹,

Isin²,

Castagnoli³

et al. 2011

Drug Metab Dispos

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ABSTRACT:In the present work, the characterization of the biotransformation and bioactivation pathways of the cannabinoid receptor 1 antagonist rimonabant (Acomplia) is described. Rimonabant was approved in Europe in 2006 for the treatment of obesity but was withdrawn in 2008 because of a significant drug-related risk of serious psychiatric disorders. The aim of the present work is to characterize the biotransformation and potential bioactivation pathways of rimonabant in vitro in human and rat liver microsomes. The observation of a major iminium ion metabolite led us to perform reactive metabolite trapping, covalent binding to proteins, and time-dependent inhibition of cytochrome P450 3A4 studies. The major biotransformation pathways were oxidative dehydrogenation of the piperidinyl ring to an iminium ion, hydroxylation of the 3 position of the piperidinyl ring, and cleavage of the amide linkage. In coincubations with potassium cyanide, three cyanide adducts were detected. A high level of covalent binding of rimonabant in human liver microsomes was observed (920 pmol equivalents/mg protein). In coincubations with potassium cyanide and methoxylamine, the covalent binding was reduced by approximately 40 and 30%, respectively, whereas GSH had no significant effect on covalent binding levels. Rimonabant was also found to inhibit cytochrome P450 3A4 irreversibly in a time-dependent manner. In view of these findings, it is noteworthy that, to date, no toxicity findings related to the formation of reactive metabolites from rimonabant have been reported.

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Section: Introductionmentioning

confidence: 99%

Bioactivation Pathways of the Cannabinoid Receptor 1 Antagonist Rimonabant

Bergström¹,

Isin²,

Castagnoli³

et al. 2011

Drug Metab Dispos

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“…The procedure used for the quantification of APAP is similar to that previously described (Shenton et al 2004). Briefly, a reversedphase HPLC assay was used, in which the mobile phase was 5% acetonitrile and 95% 5 mM sodium sulfate/20 mM potassium phosphate buffer (pH 3.2) with a flow rate of 1.2 mL/min.…”

Section: Serum Metabolite Quantificationmentioning

confidence: 99%

Mouse population-guided resequencing reveals that variants in CD44 contribute to acetaminophen-induced liver injury in humans

Harrill¹,

Watkins

Su³

et al. 2009

Genome Res.

169

128

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Interindividual variability in response to chemicals and drugs is a common regulatory concern. It is assumed that xenobiotic-induced adverse reactions have a strong genetic basis, but many mechanism-based investigations have not been successful in identifying susceptible individuals. While recent advances in pharmacogenetics of adverse drug reactions show promise, the small size of the populations susceptible to important adverse events limits the utility of whole-genome association studies conducted entirely in humans. We present a strategy to identify genetic polymorphisms that may underlie susceptibility to adverse drug reactions. First, in a cohort of healthy adults who received the maximum recommended dose of acetaminophen (4 g/d 3 7 d), we confirm that about one third of subjects develop elevations in serum alanine aminotransferase, indicative of liver injury. To identify the genetic basis for this susceptibility, a panel of 36 inbred mouse strains was used to model genetic diversity. Mice were treated with 300 mg/kg or a range of additional acetaminophen doses, and the extent of liver injury was quantified. We then employed whole-genome association analysis and targeted sequencing to determine that polymorphisms in Ly86, Cd44, Cd59a, and Capn8 correlate strongly with liver injury and demonstrated that dose-curves vary with background. Finally, we demonstrated that variation in the orthologous human gene, CD44, is associated with susceptibility to acetaminophen in two independent cohorts. Our results indicate a role for CD44 in modulation of susceptibility to acetaminophen hepatotoxicity. These studies demonstrate that a diverse mouse population can be used to understand and predict adverse toxicity in heterogeneous human populations through guided resequencing.

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“…IDR are often quite serious and sometimes fatal, and the liver has been a frequent target. Mechanisms underlying these reactions remain unknown, and models to predict hepatic IDR are lacking (Park et al, 2000;Shenton et al, 2004). Thus, the occurrence of IDR remains a perplexing human health problem and a significant economic problem for the pharmaceutical industry, because they often result in the removal of a drug from the market after significant resources have been spent on the discovery, development, and marketing of the compound.…”

mentioning

confidence: 99%

Microarray Analysis of Lipopolysaccharide Potentiation of Trovafloxacin-Induced Liver Injury in Rats Suggests a Role for Proinflammatory Chemokines and Neutrophils

Waring

Liguori

Luyendyk

et al. 2005

J Pharmacol Exp Ther

117

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Idiosyncratic drug toxicity refers to toxic reactions occurring in a small subset of patients and usually cannot be predicted during preclinical or early phases of clinical trials. One hypothesis for the pathogenesis of hepatic idiosyncratic drug reactions is that, in certain individuals, underlying inflammation results in sensitization of the liver, such that injury occurs from an agent that typically would not cause hepatotoxicity at a therapeutic dose. We explored this possibility by cotreating rats with nonhepatotoxic doses of bacterial lipopolysaccharide (LPS) and trovafloxacin (TVX), a drug that caused idiosyncratic hepatotoxicity in humans. The combination of LPS and TVX resulted in hepatotoxicity in rats, as determined by increases in serum alanine aminotransferase activity and hepatocellular necrosis, which were not observed with either agent alone. In contrast, treatment with LPS and levofloxacin, a fluoroquinolone without human idiosyncratic liability, did not result in these changes. Liver gene expression analysis identified unique changes induced by the combination of TVX and LPS, including enhanced expression of chemokines, suggestive of liver neutrophil (PMN) accumulation and activation. Consistent with a role for PMN in the hepatotoxicity induced by LPS/TVX, prior depletion of PMN attenuated the liver injury. The results suggest that gene expression profiles predictive of idiosyncratic liability can be generated in rats cotreated with LPS and drug. Furthermore, they identify gene expression changes that could be explored as biomarkers for idiosyncratic toxicity and lead to enhanced understanding of the mechanism(s) underlying hepatotoxicity induced by TVX.

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Animal models of idiosyncratic drug reactions

Cited by 90 publications

References 79 publications

Bioactivation Pathways of the Cannabinoid Receptor 1 Antagonist Rimonabant

Bioactivation Pathways of the Cannabinoid Receptor 1 Antagonist Rimonabant

Mouse population-guided resequencing reveals that variants in CD44 contribute to acetaminophen-induced liver injury in humans

Microarray Analysis of Lipopolysaccharide Potentiation of Trovafloxacin-Induced Liver Injury in Rats Suggests a Role for Proinflammatory Chemokines and Neutrophils

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