Idiosyncratic Drug Reactions Research Articles

Use of Structural Alerts for Reactive Metabolites in the Application SpotRM.

Reactive metabolite (RM) formation is widely accepted as playing a crucial role in causing idiosyncratic adverse drug reactions (IADRs), where the liver is most affected. An important goal of drug design is to avoid selection of drug candidates giving rise to RMs and therefore risk causing problems later on involving IADRs. The simplest, initial approach is to avoid test structures that have substructures known or strongly suspected to be associated with IADRs. However, as is evident from the many case reports of IADRs, in most cases a clear association with any (bio)chemical mechanism is lacking, which makes it hard to establish any structure-toxicity relationship. Separate studies of RM formation, in vitro and in vivo, have led to likely evidence and to establishing many structural alerts (SAs) that can be used for fast selection/deselection of planned test compounds. As a background to a discussion of the concept, 25 kinase inhibitor drugs with known problems of hepatotoxicity were probed against a set of SAs contained in the application SpotRM. A clear majority of the probed drugs show liabilities as evident by being flagged by more than one of the fairly established types of SAs. At the same time, no clear SAs were found in three drugs, which is discussed in the broader context of usefulness and selection tactics of SAs in drug design.

The use of PD-1 functional knockout rats to study idiosyncratic adverse reactions to nevirapine.

Idiosyncratic drug reactions (IDRs) are associated with significant patient morbidity/mortality and lead to considerable drug candidate attrition in drug development. Their idiosyncratic nature makes the study of IDRs difficult. In particular, nevirapine is associated with a relatively high risk of serious skin rash and liver injury. We previously found that nevirapine causes a similar skin rash in female Brown Norway rats, but these animals do not develop significant liver injury. Programmed cell death protein-1 (PD-1) is an immune checkpoint involved in immune tolerance, and anti-PD-1 antibodies have been used to treat cancer. However, they increase the risk of liver injury caused by co-administered drugs. We found that PD-1-/- mice are more susceptible to drug-induced liver injury, but PD-1-/- mice are not a good model for all drugs. In particular, they do not develop a skin rash when treated with nevirapine, at least in part because they lack the sulfotransferase in their skin that forms the reactive metabolite responsible for the rash. Therefore, we developed a PD-1 mutant (PD-1m/m) rat, with an excision in the ligand-binding domain of PD-1, to test whether nevirapine would cause a more serious skin rash in these animals. The PD-1m/m rat was based on a Sprague Dawley background, which has a lower incidence of skin rash than Brown Norway rats. The treated PD-1m/m rats developed more severe liver injury than PD-1-/- mice, but in contrast to expectations, they did not develop a skin rash. Functional knockouts provide a unique tool to study the mechanisms of IDRs.

Minocycline-induced drug reaction with eosinophilia and systemic symptoms (DRESS) masquerading as acute leukemia.

Drug reaction with eosinophilia and systemic symptoms (DRESS) is an idiosyncratic drug reaction characterized by fever, rash, and lymphadenopathy associated with atypical lymphocytosis and eosinophilia. Visceral organ involvement is also seen and hence it often mimics hematolymphoid malignancies. A 19-year-old girl presented with generalized pruritic rash, fever, lymphadenopathy, and lymphocytosis. Subsequently, she developed respiratory distress with a fall in SpO2. Flow cytometry, bone marrow studies, and infectious workup were normal. Skin biopsy and clinical assessment criteria established the diagnosis of DRESS secondary to minocycline intake. Discontinuation of the offending drug is most important to abet the hypersensitivity reaction. Visceral organ involvement requires the use of steroids and immunosuppressive agents. Our patient responded well to treatment and is presently symptom-free and on follow-up for the last 6 months.

The role of corticosterone in nevirapine-induced idiosyncratic drug-induced liver injury.

Nevirapine, an antiretroviral used in the treatment of HIV, is associated with idiosyncratic drug-induced liver injury (IDILI), a potentially life-threatening adverse drug reaction. Its usage has decreased due to this concern, but it is still widely used in lower-resource settings. In general, the mechanisms underlying idiosyncratic drug reactions (IDRs) are poorly understood, but evidence indicates that most are immune-mediated. There is very limited understanding of the early immune response following administration of drugs associated with IDRs, which likely occurs due to reactive metabolite formation. In this work, we aimed to characterize the links between covalent binding of nevirapine, the development of an early immune response, and the subsequent liver injury using a mouse model. We describe initial attempts to characterize an early immune response to nevirapine followed by the discovery that nevirapine induced the release of corticosterone. Corticosterone release was partially associated with the degree of drug covalent binding in the liver but was also likely mediated by additional mechanisms at higher drug doses. Transcriptomic analysis confirmed metabolic activation, glucocorticoid signaling, and decreased immune activation; GDF-15 also warrants further investigation as part of the immune response to nevirapine. Finally, glucocorticoid blockade preceding the first dose of nevirapine attenuated nevirapine-induced liver injury at 3 weeks, suggesting that acute glucocorticoid signaling is harmful in the context of nevirapine-induced liver injury. This work demonstrates that nevirapine induces acute corticosterone release, which contributes to delayed-onset liver injury. It also has implications for screening drug candidates for IDILI risk and preventing nevirapine-induced IDILI.

De-risking idiosyncratic adverse drug reactions and toxicities in drug discovery utilizing a qualitative in-vitro high-throughput reactive metabolite trapping method

De-risking idiosyncratic adverse drug reactions and toxicities in drug discovery utilizing a qualitative in-vitro high-throughput reactive metabolite trapping method

Study of clinical profile and outcome of children presented with poisoning in tertiary care hospital

Background: Poisoning is a common paediatric emergency. Worldwide estimate suggests that the rate of poisoning in under 20 years is 1.8 per one lakh population and for India it ranges between 0.6 to 11.6%. Methods: The study was conducted at B. J. Medical College Ahmedabad and Civil Hospital, Ahmedabad. A prospective analytical study consisting of total 110 patients, admitted in the intensive care unit during the period from June 2018 to November 2018 with inclusion criterion of children <12 years of age, presented with history of consumption of poisonous substances/insect bite irrespective of signs and symptoms excluding cases of food poisoning and idiosyncratic drug reactions. Detailed proforma was filled after taking necessary consent from the parents. Routine investigations and gastric samples for forensic analysis were sent in all irrespective of type or route of poisoning. Specific investigations done wherever required. Analysis of outcomes done using chi square. Results: The most common age group was 3-6 years with male to female ratio of 1.5:1. 99.1% poisoning were accidental with hydrocarbon poisoning being the most common of all (27.2%), followed by household substance poisoning in 20.9%. Snakebite was the most common insect bite (10.9%). The average duration of stay was 3.9 days, 8.1% children died with maximum mortality happened in children presented after 6 hours of intoxication. Conclusions: Management of poisoning requires immediate advice and first aid, followed by a directed treatment. Decontamination, enhanced elimination, antidotes, and supportive care are commonly used to manage poisoning cases.

Involvement of Extracellular Vesicles in the Proinflammatory Response to Clozapine: Implications for Clozapine-Induced Agranulocytosis.

Most idiosyncratic drug reactions (IDRs) appear to be immune-mediated, but mechanistic events preceding severe reaction onset remain poorly defined. Damage-associated molecular patterns (DAMPs) may contribute to both innate and adaptive immune phases of IDRs, and changes in extracellular vesicle (EV) cargo have been detected post-exposure to several IDR-associated drugs. To explore the hypothesis that EVs are also a source of DAMPs in the induction of the immune response preceding drug-induced agranulocytosis, the proteome and immunogenicity of clozapine- (agranulocytosis-associated drug) and olanzapine- (non-agranulocytosis-associated drug) exposed EVs were compared in two preclinical models: THP-1 macrophages and Sprague-Dawley rats. Compared with olanzapine, clozapine induced a greater increase in the concentration of EVs enriched from both cell culture media and rat serum. Moreover, treatment of drug-naïve THP-1 cells with clozapine-exposed EVs induced an inflammasome-dependent response, supporting a potential role for EVs in immune activation. Proteomic and bioinformatic analyses demonstrated an increased number of differentially expressed proteins with clozapine that were enriched in pathways related to inflammation, myeloid cell chemotaxis, wounding, transforming growth factor-β signaling, and negative regulation of stimuli response. These data indicate that, although clozapine and olanzapine exposure both alter the protein cargo of EVs, clozapine-exposed EVs carry mediators that exhibit significantly greater immunogenicity. Ultimately, this supports the working hypothesis that drugs associated with a risk of IDRs induce cell stress, release of proinflammatory mediators, and early immune activation that precedes severe reaction onset. Further studies characterizing EVs may elucidate biomarkers that predict IDR risk during development of drug candidates. SIGNIFICANCE STATEMENT: This work demonstrates that clozapine, an idiosyncratic drug-induced agranulocytosis (IDIAG)-associated drug, but not olanzapine, a safer structural analogue, induces an acute proinflammatory response and increases extracellular vesicle (EV) release in two preclinical models. Moreover, clozapine-exposed EVs are more immunogenic, as measured by their ability to activate inflammasomes, and contain more differentially expressed proteins, highlighting a novel role for EVs during the early immune response to clozapine and enhancing our mechanistic understanding of IDIAG and other idiosyncratic reactions.

The development and characterization of a CRISPR/Cas9-mediated PD-1 functional knockout rat as a tool to study idiosyncratic drug reactions.

Idiosyncratic drug reactions are rare but serious adverse drug reactions unrelated to the known therapeutic properties of the drug and manifest in only a small percentage of the treated population. Animal models play an important role in advancing mechanistic studies examining idiosyncratic drug reactions. However, to be useful, they must possess similarities to those seen clinically. Although mice currently represent the dominant mammalian genetic model, rats are advantageous in many areas of pharmacologic study where their physiology can be examined in greater detail and is more akin to that seen in humans. In the area of immunology, this includes autoimmune responses and susceptibility to diabetes, in which rats more accurately mimic disease states in humans compared with mice. For example, oral nevirapine treatment can induce an immune-mediated skin rash in humans and rats, but not in mice due to the absence of the sulfotransferase required to form reactive metabolites of nevirapine within the skin. Using CRISPR-mediated gene editing, we developed a modified line of transgenic rats in which a segment of IgG-like ectodomain containing the core PD-1 interaction motif containing the native ligand and therapeutic antibody domain in exon 2 was deleted. Removal of this region critical for mediating PD-1/PD-L1 interactions resulted in animals with an increased immune response resulting in liver injury when treated with amodiaquine.

A Rare Case of Rifampicin-induced Drug Reaction with Eosinophilia and Systemic Symptoms Syndrome

ABSTRACT Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is an idiosyncratic adverse drug reaction that can be lethal in up to 20% cases. The commonest culprit drug includes phenytoin, allopurinol, phenobarbital, sulfasalazine and lamotrigine. DRESS syndrome due to antitubercular medicines is rarely reported. In India despite the widespread use of antitubercular medicines, only few cases of DRESS syndrome have been reported. Here we report an interesting case of a 23 year old girl who presented to us with complaints of high grade fever, cough, GI discomfort, numbness, severe pruritus and burning skin sensation. She was receiving antitubercular medicines for tubercular pleural effusion for the last three weeks. She was hospitalised for a suspected adverse drug reaction which was diagnosed as DRESS syndrome on the basis of RegiSCAR criteria. On re-challenge testing the culprit drug was found to be rifampicin. In this case the severity of skin involvement was much higher as compared to organ involvement.

THU449 An Unexpected Case Of Cutaneous Leukocytoclastic Vasculitis Following Zoledronic Acid Infusion

Abstract Disclosure: B. Zahedi: None. Z.S. Wallace: None. M.M. Cote: None. E.W. Yu: Grant Recipient; Self; Amgen Inc. Background: Zoledronic acid is a potent amino-bisphosphonate frequently used in the treatment of osteoporosis. We report a case of small-vessel vasculitis with cutaneous manifestations occurring after zoledronic acid infusion, previously not reported in the literature. Clinical case: A 58-year old woman with a history of sleeve gastrectomy 1.5 years prior was treated for bone protection with an intravenous infusion of zoledronic acid (Zol) 5mg. This was the patient’s first exposure to a bisphosphonate medication. Within minutes of the infusion, she developed a single episode of diffuse watery diarrhea. Although GI symptoms resolved quickly, within a few hours she experienced generalized myalgias and skin tenderness in her abdomen and extremities, for which she took NSAIDs. These symptoms progressed in severity over the next 3-5 days, manifesting as bilateral hand and lower extremity edema and erythema; no fever/chills/sweats, mucocutaneous ulcers, or urinary symptoms were present. By Day 5, she developed palpable purpura without blanching above the ankles and extending to the knees. By Day 7, prednisone 60mg was started. Prior to Zol, labs showed sufficient 25-hydroxyvitamin D, normal calcium, renal and liver function. On Days 10 and 14, labs revealed AST and ALT, twice and thrice the upper limit of normal respectively. Other notable labs included normal UA, Ca, WBC, eGFR, nonelevated ESR/CRP, and a negative work up for an underlying infectious, inflammatory, ANCA-associated, hypocomplementemic or autoimmune process. Cutaneous findings resolved within 3 weeks of Zol, and transaminitis and edema resolved by week 4. In the setting of a negative lab workup and typical palpable purpura, the patient was diagnosed with leukocytoclastic cutaneous vasculitis (LCV), likely induced by Zol (Naranjo score of 5 consistent with probable adverse drug reaction). Although IgA-mediated Henoch-Schonlein Purpura (HSP) cannot be definitively ruled out in absence of a skin biopsy, the patient did not exhibit other clinical features of HSP, and the timeline is highly suggestive of an idiosyncratic drug reaction whereby Zol acted as a hapton to stimulate an immunologic vasculitis response. Up to 50% of patients with LCV have systemic involvement (renal, GI, pulmonary, cardiac or CNS). Cutaneous LCV usually carries a favorable prognosis after treatment with glucocorticoids. On review of the literature, no prior cases of bisphosphonate-induced LCV have been reported, although there are few cases of giant cell arteritis, uveitis and urticarial vasculitis with bisphosphonate therapy. Conclusions: This is the first case demonstrating cutaneous manifestations consistent with leukocytoclastic vasculitis due to zoledronic acid infusion, which was successfully managed with NSAIDs and glucocorticoids. Clinicians should be aware that LCV may be a rare hypersensitivity complication of Zol. Presentation: Thursday, June 15, 2023

Consideration of Nevirapine Analogs To Reduce Metabolically Linked Hepatotoxicity: A Cautionary Tale of the Deuteration Approach.

Idiosyncratic drug reactions (IDRs) in their most deleterious form can lead to serious medical complications and potentially fatal events. Nevirapine (NVP), still widely used in developing countries for combinatorial antiretroviral and prophylactic therapies against HIV infection, represents a prototypical example of IDRs causing severe skin rashes and hepatotoxicity. Complex metabolic pathways accompanied by production of multiple reactive metabolites often complicate our understanding of IDR's origin. While assessment of NVP analogs has helped characterize the pathways involved in IDRs for NVP, which are largely driven by metabolism at the 12-methyl position, it has yet to be investigated if some of these analogs could be valuable replacement drugs with reduced reactive metabolite properties and drug-drug interaction (DDI) risks. Here, we evaluated a set of eight NVP analogs, including the deuterated 12-d3-NVP and two NVP metabolites, for their efficacy and inhibitory potencies against HIV reverse transcriptase (HIV-RT). A subset of three analogs, demonstrating >85% inhibition for HIV-RT, was further assessed for their hepatic CYP induction-driven DDI risks. This led to a closer investigation of the inactivation properties of 12-d3-NVP for hepatic CYP3A4 and a comparison of its propensity in generating reactive metabolite species. The metabolic shift triggered with 12-d3-NVP, increasing formation of the 2-hydroxy and glutathione metabolites, emphasized the importance of the dynamic balance between induction and metabolism-dependent inactivation of CYP3A4 and its impact on clearance of NVP during treatment. Unfortunately, the strategy of incorporating deuterium to reduce NVP metabolism and production of the electrophile species elicited opposite results, illustrating the great challenges involved in tackling IDRs through deuteration.

DRESS Syndrome in ICU : A Diagnostic Dilemma.

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome can be severe and life-threatening especially in critical care setting if not diagnosed and treated in time. DRESS syndrome is an idiosyncratic drug reaction characterized by rash, fever, eosinophilia, lymphadenopathy and internal organ. Regis CAR (European Registry of Severe Cutaneous Adverse Reaction) scoring system is used for its diagnosis. Diagnosis of this syndrome can be challenging in critical care setting due to nonspecific clinical features, multiple confounding factors, use of polypharmacy, and its resemblance with sepsis and septic shock of varied etiologies. We report a case of 15-year-old boy who developed this syndrome after starting sulfasalazine, HCQ and NSAIDS all together, one month back for treatment of ankylosing spondylitis. This case report focuses on early suspicion and identification of this syndrome in critical care setting. This in turn should help in effective treatment of the illness by stopping offending drugs and timely initiation of steroid therapy. Further it may help in judicious use of antibiotics by holding irrational use of these drugs.

Synergistic Effects of Vitis vinifera L. and Centella asiatica against CCl4-Induced Liver Injury in Mice.

Liver injury can be acute or chronic, resulting from a variety of factors, including viral hepatitis, drug overdose, idiosyncratic drug reaction, or toxins, while the progression of pathogenesis in the liver rises due to the involvement of numerous cytokines and growth factor mediators. Thus, the identification of more effective biomarker-based active phytochemicals isolated from medicinal plants is a promising strategy to protect against CCl4-induced liver injury. Vitis vinifera L. (VE) and Centella asiatica (CE) are well-known medicinal plants that possess anti-inflammatory and antioxidant properties. However, synergism between the two has not previously been studied. Here, we investigated the synergistic effects of a V. vinifera L. (VE) leaf, C. asiatica (CE) extract combination (VCEC) against CCl4-induced liver injury. Acute liver injury was induced by a single intraperitoneal administration of CCl4 (1 mL/kg). VCEC was administered orally for three consecutive days at various concentrations (100 and 200 mg/kg) prior to CCl4 injection. The extent of liver injury and the protective effects of VCEC were evaluated by biochemical analysis and histopathological studies. Oxidative stress was evaluated by measuring malondialdehyde (MDA) and glutathione (GSH) levels and Western blotting. VCEC treatment significantly reduced serum transaminase levels (AST and ALT), tumor necrosis factor-α (TNF-α), and reactive oxygen species (ROS). CCl4- induced apoptosis was inhibited by VCEC treatment by reducing cleaved caspase-3 and Bcl2-associated X protein (Bax). VCEC-treated mice significantly restored cytochrome P450 2E1, nuclear factor erythroid 2-related factor 2 (Nrf2), and heme oxygenase-1 (HO-1) expression in CCl4-treated mice. In addition, VCEC downregulated overexpression of proinflammatory cytokines and hepatic nuclear factor kappa B (NF-κB) and inhibited CCl4-mediated apoptosis. Collectively, VCEC exhibited synergistic protective effects against liver injury through its antioxidant, anti-inflammatory, and antiapoptotic ability against oxidative stress, inflammation, and apoptosis. Therefore, VCEC appears promising as a potential therapeutic agent for CCl4-induced acute liver injury in mice.

Relevance of Pharmacogenomics to the Safe Use of Antimicrobials.

There has been widespread implementation of pharmacogenomic testing to inform drug prescribing in medical specialties such as oncology and cardiology. Progress in using pharmacogenomic tests when prescribing antimicrobials has been more limited, though a relatively large number of pharmacogenomic studies on aspects such as idiosyncratic adverse drug reactions have now been performed for this drug class. Currently, there are recommendations in place from either National Regulatory Agencies and/or specialist Pharmacogenomics Advisory Groups concerning genotyping for specific variants in MT-RNR1 and CYP2C19 before prescribing aminoglycosides and voriconazole, respectively. Numerous additional pharmacogenomic associations have been reported concerning antimicrobial-related idiosyncratic adverse drug reactions, particularly involving specific HLA alleles, but, to date, the cost-effectiveness of genotyping prior to prescription has not been confirmed. Polygenic risk score determination has been investigated to a more limited extent but currently suffers from important limitations. Despite limited progress to date, the future widespread adoption of preemptive genotyping and genome sequencing may provide pharmacogenomic data to prescribers that can be used to inform prescribing and increase the safe use of antimicrobials.

Piperazine ring toxicity in three novel anti-breast cancer drugs: an in silico and in vitro metabolic bioactivation approach using olaparib as a case study.

The metabolic activation of small-molecule drugs into electrophilic reactive metabolites is widely recognized as an indicator of idiosyncratic adverse drug reactions (IADRs). Three novel anti-breast cancer drugs containing piperazine rings, ribociclib (Kisqali®, RCB), abemaciclib (Verzenio®, ABC), and olaparib (Lynparza®, OLP), were selected to study the effect of different chemical environment on the piperazine ring activation using in silico and in vitro metabolic experiments. ABC and RCB were previously studied and we noticed the piperazine ring in ABC could be strongly bioactivated generating more reactive intermediates than piperazine ring in RCB. OLP was further used as a case study to show the power of in silico software to predict the piperazine ring activation that was approved using in vitro experiments. Initially, predictions of susceptible sites in the metabolism and reactivity pathways were performed using the StarDrop P450 model and XenoSite reactivity tool, respectively. Later, in vitro OLP metabolites were characterized based on rat liver microsomes (RLMs) using KCN (trapping agent) using LC-MS/MS. The main goal of the current study was to answer the question of whether the presence of a piperazine ring in the chemical structure should be always considered a structural alert. Piperazine ring in RBC and ABC was bioactivated through a metabolic sequence that involves the hydroxylation of α-carbon to the tertiary nitrogen atoms of the piperazine ring. In the case of OLP, no cyano adduct was formed due to the presence of two carbonyl groups attached to the two nitrogen atoms of the piperazine ring (neutral amide groups). From the results, piperazine ring in certain cases should not be considered as a structural alert as in the case of OLP due to the presence of two electron withdrawing group that stops the proposed toxicity. Also blocking the bioactive center (α-carbon) using steric hindrances such as methyl group, also the isosteric replacement of α-carbon hydrogen with fluoro atom can aid in reducing the toxic side effects of ABC and RCB. These experiments were done in vitro through incubation with RLMs in the presence of KCN. Also, the results are supported by data generated from in silico software. In the future, drug discovery studies using this concept could be undertaken, allowing for the development of new drugs with reasonable safety profiles. Overall, in vitro RLMs incubations and in silico experiments were able to predict successfully that the piperazine ring should not always be considered a structural alert.

Drug Rash with Eosinophilia and Systemic Symptoms (DRESS Syndrome).

DRESS syndrome is an idiosyncratic drug reaction and potentially life-threatening. The authors report a case of this syndrome presenting with fever, rash, mucosal involvement, liver and muscle involvement associated with moxifloxacin treatment.

Pirfenidone Induced Dress Syndrome Post COVID-19 InfectionAn Unusual Case Report

Drug Reaction, Eosinophilia and Systemic Symptoms (DRESS) is an idiosyncratic drug reaction characterised by extensive skin rash, fever, lymphadenopathy and internal organ involvement. Since eosinophilia may or may not always be present, the condition is now more preferably called Drug-Induced Hypersensitivity Syndrome (DIHS). The authors here report a case of DRESS syndrome, secondary to Pirfenidone, an anti-fibrotic given to the patient for post COVID-19 fibrosis. The 51 years old male patient, presented with multiple pus-filled erythematous lesions, 3 months after the initiation of Pirfenidone. Laboratory results showed deranged liver and renal functioning, along with reactive Dengue Nonstructural protein 1(NS 1) antigen. He showed significant improvement in the dermatological lesions and multisystem laboratory involvement with tapering doses of steroids.

ATT associated DRESS syndrome in a patient of multidrug resistant tuberculosis diagnosed on lymph node FNAC

Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a rare type of idiosyncratic drug reaction. It is usually associated with antiepileptic drugs. It can also be associated with first line anti-tubercular drugs (ATDs), antibiotics, herbal medicines and many other drugs. We report a case of DRESS syndrome presented with erythematous lesions all over the body following the intake of second line ATDs for multi drug resistant tuberculosis. FNAC was done from the enlarged inguinal lymph node which revealed the presence of atypical lymphocytes. Clinical and other supportive features confirmed the diagnosis of DRESS syndrome.

SOC-IV-04 DAMPening the immune response to clozapine: the role of reactive metabolites in idiosyncratic drug reactions

SOC-IV-04 DAMPening the immune response to clozapine: the role of reactive metabolites in idiosyncratic drug reactions

Non-innocuous Consequences of Metabolic Oxidation of Alkyls on Arenes.

Reactive metabolite (RM) formation is widely accepted as playing a pivotal role in causing adverse idiosyncratic drug reactions, with most attention paid to drug-induced liver injury. Mechanisms of RM formation are determined by the drug's properties in relation to human enzymes transforming the drug. This Perspective focuses on enzymatic oxidation of alkyl groups on aromatics leading to quinone methides and benzylic alcohol sulfates as RMs, a topic that has not received very much attention. Unlike previous overviews, we will include in our Perspective several fulvene-like methides such as 3-methyleneindole. We also speculate that a few older drugs may form non-reported methides of this class. In addition, we report a few guiding DFT calculations of changes in free energy on going from a benzylic alcohol to the corresponding methide. Particularly facile reactions of 2-aminothiazole-5-methanol and 4-aminobenzyl alcohol are noted.