A Comprehensive Listing of Bioactivation Pathways of Organic Functional Groups

Abstract

The occurrence of idiosyncratic adverse drug reactions during late clinical trials or after a drug has been released can lead to a severe restriction in its use and even in its withdrawal. Metabolic activation of relatively inert functional groups to reactive electrophilic intermediates is considered to be an obligatory event in the etiology of many drug-induced adverse reactions. Therefore, a thorough examination of the biochemical reactivity of functional groups/structural motifs in all new drug candidates is essential from a safety standpoint. A major theme attempted in this review is the comprehensive cataloging of all of the known bioactivation pathways of functional groups or structural motifs commonly utilized in drug design efforts. Potential strategies in the detection of reactive intermediates in biochemical systems are also discussed. The intention of this review is not to "black list" functional groups or to immediately discard compounds based on their potential to form reactive metabolites, but rather to serve as a resource describing the structural diversity of these functionalities as well as experimental approaches that could be taken to evaluate whether a "structural alert" in a new drug candidate undergoes bioactivation to reactive metabolites.

Mitochondrial superoxide dismutase and glutathione peroxidase in idiosyncratic drug-induced liver injury

“…The electrophilic nature of these reactive intermediates make them prone to form adducts with DNA and cellular proteins as well as glutathione, that may proceed to liver injury. 11 Glutathione adduct formation can be viewed as a potential detoxification pathway; however, this process also depletes glutathione stores, thus limiting its use as a reducing equivalent, which in conjunction with additional ROS sources could have damaging consequences. In addition, quinones are highly redox active compounds that can redox cycle with their corresponding semiquinones and hydroquinones to form ROS, 11 thus providing an additional source of intracellular ROS.…”

“…Many drugs undergo bioactivation in the liver that may or may not lead to the formation of reactive intermediates or metabolites, such as quinones, epoxides, and diazenes, that could potentially cause cellular damage. 11,12 Focusing on the chemical structure of reactive metabolites/intermediates formed rather than the parent drug may thus provide better insight into the underlying mechanism and equivalent determinants of DILI development. Both of the two groups of reactive intermediates focused on in this study displayed a significant association between the SOD2 Ala/Ala genotype and the risk of developing cholestatic/mixed type of liver injury.…”

“…10 The aforementioned drugs were also classified according to their ability to form reactive intermediates (quinones, quinone methides, quinone imines, epoxides, S-oxides, diazenes, nitroanion radicals, and iminium ions) and known mitochondrial hazards based on thorough searches of published information. [11][12][13][14] Patients who gave informed consent and for whom a blood sample was available were considered eligible only if the causality assessment score was ''definite'' or ''probable.'' Excluded were cases secondary to drug overdoses (acetaminophen) and occupational exposure to toxins.…”

Mechanisms of cytochrome P450 substrate oxidation: MiniReview

“…However, these can all be rationalized in the context of the proposed perferryl oxidation chemistry discussed above, and the reader is referred to more extensive reviews published elsewhere [8,36,37]. In a number of cases the, oxidized products are electrophilic and the binding of these to tissue nucleophiles can be related to toxicity ( Figure 5) [38][39][40][41], although demonstration of a causal relationship has proven difficult [42].…”

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“…An ADMET profiling using a traffic lights representation: An oral bioavailability evaluation considering Lipinski, Veber, Egan, and Bayer rules. A drug safety profiling considering the GSK 4/400 rule according to Gleeson et al, [42] the Pfizer 3/75 rule, [43] a phospholipidosis inducing estimation according to Przybylak et al, [44] and finally the Lilly MedChem Rules rating. [45] A compound positioning within the Pfizer 3/75 rule, [46] according to Hughes et al [ Table 8].…”