Structure Toxicity Relationships - How Useful Are They in Predicting Toxicities of New Drugs?

Nelson, Sidney D.

doi:10.1007/978-1-4615-0667-6_4

Cited by 45 publications

(23 citation statements)

References 49 publications

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“…Evidence from such investigations suggests that bioactivation of drugs to reactive intermediates constitutes a rate-limiting step in the etiology of some ADRs (Nelson, 2001;Evans et al, 2004;Park et al, 2005;Kalgutkar et al, 2005a;Kalgutkar and Soglia, 2005). Information to qualify certain functional groups as "structural alerts" or "toxicophores" also has been inferred from such studies based on myriad examples of protoxins containing these motifs, which are bioactivated to reactive metabolites (Kalgutkar et al, 2005a).…”

mentioning

confidence: 99%

Comparison of the Bioactivation Potential of the Antidepressant and Hepatotoxin Nefazodone with Aripiprazole, a Structural Analog and Marketed Drug

Bauman

Frederick²,

Sawant³

et al. 2008

Drug Metab Dispos

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ABSTRACT:In vitro metabolism/bioactivation of structurally related central nervous system agents nefazodone (hepatotoxin) and aripiprazole (nonhepatotoxin) were undertaken in human liver microsomes in an attempt to understand the differences in toxicological profile. NADPH-supplemented microsomal incubations of nefazodone and glutathione generated conjugates derived from addition of thiol to quinonoid intermediates. Inclusion of cyanide afforded cyano conjugates to iminium ions derived from ␣-carbon oxidation of the piperazine ring in nefazodone and downstream metabolites. Although the arylpiperazine motif in aripiprazole did not succumb to bioactivation, the dihydroquinolinone group was bioactivated via an intermediate monohydroxy metabolite to a reactive species, which was trapped by glutathione. Studies with synthetic dehydroaripiprazole metabolite revealed an analogous glutathione conjugate with molecular weight 2 Da lower. Based on the proposed structure of the glutathione conjugate(s), a bioactivation sequence involving aromatic ortho-or para-hydroxylation on the quinolinone followed by oxidation to a quinone-imine was proposed. P4503A4 inactivation studies in microsomes indicated that, unlike nefazodone, aripiprazole was not a time-and concentration-dependent inactivator of the enzyme. Overall, these studies reinforce the notion that not all drugs that are bioactivated in vitro elicit a toxicological response in vivo. A likely explanation for the markedly improved safety profile of aripiprazole (versus nefazodone) despite the accompanying bioactivation liability is the vastly improved pharmacokinetics (enhanced oral bioavailability, longer elimination half-life) due to reduced P4503A4-mediated metabolism/bioactivation, which result in a lower daily dose (5-20 mg/day) compared with nefazodone (200-400 mg/day). This attribute probably reduces the total body burden to reactive metabolite exposure and may not exceed a threshold needed for toxicity.

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mentioning

confidence: 99%

Comparison of the Bioactivation Potential of the Antidepressant and Hepatotoxin Nefazodone with Aripiprazole, a Structural Analog and Marketed Drug

Bauman

Frederick²,

Sawant³

et al. 2008

Drug Metab Dispos

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“…Several drugs that contain structural alerts are associated with IADRs and evidence for RM formation (characterization of adducts with biological nucleophiles, such as GSH and/or covalent binding to HLMs) with these drugs has been demonstrated (Kalgutkar & Didiuk, 2009;Kalgutkar & Soglia, 2005;Nelson, 1982Nelson, , 2001b. Additionally, several cases exist in which replacement of the RM forming offending moiety has resulted in drugs with better safety profile (Kalgutkar, 2011).…”

Section: Interpretation Of a ''Positive Signal'' (Detection Of A Gsh mentioning

confidence: 95%

Practical approaches to resolving reactive metabolite liabilities in early discovery

Dalvie

Kalgutkar

Chen

2014

Drug Metabolism Reviews

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Idiosyncratic toxicity is one of the principal causes for withdrawal of marketed drugs after launch. Circumstantial evidence suggests that several drug-induced adverse effects are a result of transformation of a drug to electrophilic reactive metabolites (RMs) that can covalently bind to vital macromolecules in the body. Strategies have been implemented in early discovery to examine (and minimize) the formation of RMs. A common technique involves incubation of a new chemical entity with NADPH-supplemented human liver microsomes (HLMs) in the presence of soft nucleophilic trapping agents, such as glutathione (GSH) or N-acetylcysteine (NAC). Advances in mass spectrometry and the advent of very sensitive mass spectrometers ensure facile identification of the resulting GSH or NAC adducts of the reactive species. Detection of sulfhydryl conjugates in in vitro incubations, however, raise more questions regarding the path forward for RM-positive drug candidates. One approach that can assist in mitigating RM formation is assessment of their total body burden. Computation of dose using in vitro intrinsic clearance (Clint), potency data (Ceff) and the fractional contribution of RM pathway (frm), can provide an initial read of the daily burden of RM. This overview attempts to provide practical ways of assessing these factors and assist in putting the risk of RM formation into perspective.

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“…One strategic change to candidate drug molecules is the complete removal of a 'structural alert' moiety undergoing bioactivation from the molecule. Structural alerts ( Table 1) are moieties contained in larger drug structures that are known to be toxicologically problematic [2,5,8,29]. In cases where a structural alert cannot be eliminated, attempts can be made to modify the structural alert by blocking or hindering the site of bioactivation, altering the electronics of the bioactivated moiety making it less prone to metabolism, or by introducing a functional group that leads to a redirected site of metabolism to an unreactive, nontoxic metabolite [14].…”

Section: P Grillomentioning

confidence: 99%

“…However, in some instances the metabolism of drugs by Phase I and/or II pathways can be toxicologically significant. A framework hypothesis introduced during the 1960s and 1970s and used to research drug-mediated toxicity proposed that some drugs cause organ toxicity or carcinogenesis after becoming metabolized to chemically reactive metabolites that react with and covalently bind to tissue macromolecules, including proteins and DNA ( Figure 1) [2,3]. Since, the major reasons for drug attrition include preclinical toxicity and human adverse events [4,5], the general opinion of drug discovery scientists is that chemically reactive metabolites are potentially toxic and therefore an unwanted attribute of candidate drugs [3,6].…”

Section: Introductionmentioning

confidence: 99%

Detecting reactive drug metabolites for reducing the potential for drug toxicity

Grillo¹

2015

Expert Opinion on Drug Metabolism & Toxicology

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Structure Toxicity Relationships - How Useful Are They in Predicting Toxicities of New Drugs?

Cited by 45 publications

References 49 publications

Comparison of the Bioactivation Potential of the Antidepressant and Hepatotoxin Nefazodone with Aripiprazole, a Structural Analog and Marketed Drug

Comparison of the Bioactivation Potential of the Antidepressant and Hepatotoxin Nefazodone with Aripiprazole, a Structural Analog and Marketed Drug

Practical approaches to resolving reactive metabolite liabilities in early discovery

Detecting reactive drug metabolites for reducing the potential for drug toxicity

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