Comprehensive kinetic and modeling analyses revealed CYP2C9 and 3A4 determine terbinafine metabolic clearance and bioactivation

Barnette, Dustyn A.; Davis, Mary A.; Flynn, Noah R.; Pidugu, Anirudh S.; Swamidass, S. Joshua; Miller, Grover P.

doi:10.1016/j.bcp.2019.113661

Cited by 13 publications

(11 citation statements)

References 15 publications

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“…Steady-state kinetics for reactions revealed the preferred bioactivation pathway among three possibilities. In follow-up studies, we determined the relative significance of cytochrome P450 isozymes contributing to terbinafine bioactivation pathways and extrapolated their relevance for the average adult (Barnette et al, 2019;Davis et al, 2019). Similarly, we studied bioactivation kinetics for a pair of NSAIDs, sudoxicam and meloxicam, to yield a thioamide protoxin and dicarbonyl co-metabolite (Barnette et al, 2020).…”

Section: Downloaded Frommentioning

confidence: 99%

Significance of Multiple Bioactivation Pathways for Meclofenamate as Revealed through Modeling and Reaction Kinetics

et al. 2020

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Meclofenamate is a non-steroidal anti-inflammatory drug used in the treatment of mild to moderate pain yet poses a rare risk of hepatotoxicity through an unknown mechanism. NSAID bioactivation is a common molecular initiating event for hepatotoxicity. Thus, we hypothesized a similar mechanism for meclofenamate and leveraged computational and experimental approaches to identify and characterize its bioactivation. Analyses employing our XenoNet model indicated possible pathways to meclofenamate bioactivation into 19 reactive metabolites subsequently trapped into glutathione adducts. We describe the first reported bioactivation kinetics for meclofenamate and relative importance of those pathways using human liver microsomes. The findings validated only four of the many bioactivation pathways predicted by modeling. For experimental studies, dansyl glutathione was a critical trap for reactive quinone metabolites and provided a way to characterize adduct structures by mass spectrometry and quantitate yields during reactions. Of the four quinone adducts, we were able to characterize structures for three of them. Based on kinetics, the most efficient bioactivation pathway led to the monohydroxy para-quinone-imine followed by the dechloro-ortho-quinone-imine. Two very inefficient pathways led to the dihydroxy ortho-quinone and a likely multiply adducted quinone. When taken together, bioactivation pathways for meclofenamate accounted for approximately 13% of total metabolism. In sum, XenoNet facilitated prediction of reactive metabolite structures while quantitative experimental studies provided a tractable approach to validate actual bioactivation pathways for meclofenamate. Our results provide a foundation for assessing reactive metabolite load more accurately for future comparative studies with other NSAIDs and drugs in general. Significance Statement Meclofenamate bioactivation may initiate hepatotoxicity yet common risk assessment approaches are often cumbersome and inefficient and yield qualitative insights that do not scale This article has not been copyedited and formatted. The final version may differ from this version.

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Section: Downloaded Frommentioning

confidence: 99%

Significance of Multiple Bioactivation Pathways for Meclofenamate as Revealed through Modeling and Reaction Kinetics

et al. 2020

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“…TP-1 and TP-7 were formed during degradation of terbinafine in the presence of UVA irradiation (Kryc of terbinafine to desmethyl terbinafine. This compound further forms 6, 6-dimethyl-2-hepten-4-ynal in the livera compound that can initiate idiosyncratic drug-induced liver toxicity (Iverson and Uetrecht 2001;Barnette et al 2019). After previous application of β-glucuronidase hydrolysis in urine and plasma, the metabolite TP-7 was determined which was also identified in mycelium (Zehender et al 1995).…”

Section: Resultsmentioning

confidence: 99%

Feasibility of the use of Lentinula edodes mycelium in terbinafine remediation

et al. 2020

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A detailed understanding of the fate of xenobiotics introduced into the environment and the mechanisms involved in their biotransformation, biodegradation, and biosorption is essential to improve the efficiency of remediation techniques. Mycoremediation is a form of bioremediation technique that has become increasingly popular in recent years as fungi are known to produce various effective extracellular enzymes that have the potential to neutralize a wide variety of xenobiotics released into the environment. Hence, mycoremediation appears to be a promising technique for the removal of a wide array of toxins and pharmaceutical residues from a damaged environment and wastewater. This study primarily aimed to investigate whether white-rot fungus (Lentinula edodes) can be utilized for the bioremediation of common antifungal agent terbinafine, which is mainly available in the market as powder or cream. The cultures of L. edodes were cultivated in the medium containing terbinafine powder or terbinafine 1% cream, each at a final concentration of 0.1 mg mL −1. The addition of terbinafine in powder form have a negative effect on biomass growth (p < 0.05). The total amount of terbinafine in the dry weight of mycelium after culture was estimated to be 7.63 ± 0.45 mg and 12.52 ± 2.46 mg for powder and cream samples, respectively. In addition, there were no traces of terbinafine in any of the samples of medium used for culturing L. edodes after the experimental duration period. The biodegradation products of terbinafine were identified for the first time using UPLC/MS/MS. The biodegradation of terbinafine resulted in the loss of 1-naphthylmethanol, which occurred via oxidative deamination, N-demethylation, or tert-butyl group hydroxylation. The results of the study demonstrate that L. edodes mycelium can be effectively used for the remediation of terbinafine.

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“…The validity of predictions was improved by using the structure inference model to filter out highly predicted sites that do not produce an inferred structure. For the experimental studies, analysis of the reactive metabolites relied on set reaction conditions and no steady-state kinetics that could be used to extrapolate the potential in vivo relevance of bioactivation pathways [16,18]. Moreover, there are no reported studies investigating and confirming that the bioactivation of isoxazole-containing molecules contributes to in vitro or in vivo toxicity.…”

Section: Advances In Isoxazole Bioactivation Studies Revealed Current Limitations Of Those Effortsmentioning

confidence: 99%

“…These computational analyses are more accessible than experiments and provide an opportunity to readily explore potential relationships between molecular structure and bioactivation that lead to testable hypotheses. In practice, we couple high throughput computational studies with experimental efforts to validate predicted relationships and reveal model shortcomings for further refinement into practical tools, as shown through our work on terbinafine [16], thiazoles [17,18], and diphenylamine nonsteroidal anti-inflammatory drugs [19]. In this study, we applied our novel computational and experimental strategy to reveal the potential bioactivation liabilities of bromodomain and extra-terminal (BET) inhibitors.…”

Section: Introductionmentioning

confidence: 99%

Bioactivation of Isoxazole-Containing Bromodomain and Extra-Terminal Domain (BET) Inhibitors

et al. 2021

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The 3,5-dimethylisoxazole motif has become a useful and popular acetyl-lysine mimic employed in isoxazole-containing bromodomain and extra-terminal (BET) inhibitors but may introduce the potential for bioactivations into toxic reactive metabolites. As a test, we coupled deep neural models for quinone formation, metabolite structures, and biomolecule reactivity to predict bioactivation pathways for 32 BET inhibitors and validate the bioactivation of select inhibitors experimentally. Based on model predictions, inhibitors were more likely to undergo bioactivation than reported non-bioactivated molecules containing isoxazoles. The model outputs varied with substituents indicating the ability to scale their impact on bioactivation. We selected OXFBD02, OXFBD04, and I-BET151 for more in-depth analysis. OXFBD’s bioactivations were evenly split between traditional quinones and novel extended quinone-methides involving the isoxazole yet strongly favored the latter quinones. Subsequent experimental studies confirmed the formation of both types of quinones for OXFBD molecules, yet traditional quinones were the dominant reactive metabolites. Modeled I-BET151 bioactivations led to extended quinone-methides, which were not verified experimentally. The differences in observed and predicted bioactivations reflected the need to improve overall bioactivation scaling. Nevertheless, our coupled modeling approach predicted BET inhibitor bioactivations including novel extended quinone methides, and we experimentally verified those pathways highlighting potential concerns for toxicity in the development of these new drug leads.

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Comprehensive kinetic and modeling analyses revealed CYP2C9 and 3A4 determine terbinafine metabolic clearance and bioactivation

Cited by 13 publications

References 15 publications

Significance of Multiple Bioactivation Pathways for Meclofenamate as Revealed through Modeling and Reaction Kinetics

Significance of Multiple Bioactivation Pathways for Meclofenamate as Revealed through Modeling and Reaction Kinetics

Feasibility of the use of Lentinula edodes mycelium in terbinafine remediation

Bioactivation of Isoxazole-Containing Bromodomain and Extra-Terminal Domain (BET) Inhibitors

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