Application of Modern Drug Metabolism Structure Determination Tools and Assays to the In Vitro Metabolism of Imiloxan

Fitch, William L.; Chen, Yuan; Liu, Liling; Paehler, Axel; Young, May

doi:10.2174/187231210791292753

Cited by 8 publications

(8 citation statements)

References 19 publications

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“…All other chemicals were purchased from commercial sources and were of the highest purity available. Generic LC/MS/MS and deuterium exchange methods on the Thermo Fisher LTQ Orbitrap, and reaction phenotyping will be published in full in an article in preparation [1].…”

Section: Methodsmentioning

confidence: 99%

“…The metabolism of ketoconazole was studied in 8 incubations, rat and human liver microsomes with added cyanide versus added glutathione at time zero and 1 hr. A standard generic acquisition method was used to generate the raw data [1]. This method generates accurate full scan mass spectra as well as accurate MS/MS spectra for the two largest ions in the full scan and low resolution spectra for the two corresponding MS 3 scans.…”

Section: Ketoconazole Metabolism In Liver Microsomesmentioning

confidence: 99%

“…While investigating the in vitro metabolism of an imidazole-containing drug [1] we noticed that the microsomal metabolism of drugs containing this functional group is surprisingly poorly studied given their importance in medicine and as inhibitors of cytochrome P450's. We chose to revisit the microsomal metabolism of ketoconazole as a representative imidazole drug.…”

Section: Introductionmentioning

confidence: 99%

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Revisiting the Metabolism of Ketoconazole Using Accurate Mass

Fitch¹,

Tran²,

Young³

et al. 2009

DML

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The microsomal metabolism of ketoconazole is revisited using accurate mass LC/MS(n) and deuterium labelling. Structures for sixteen metabolites are proposed from rat and human microsomal metabolism of commercial ketoconazole. Thirteen of the proposed structures are well determined and consistent with all data; five of the proposed structures are less certain. Ten of the metabolites are described for the first time. Reaction phenotyping shows that most of the metabolites arise from CYP3A4, the enzyme known to be well inhibited by ketoconazole.

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Section: Methodsmentioning

confidence: 99%

Section: Ketoconazole Metabolism In Liver Microsomesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Revisiting the Metabolism of Ketoconazole Using Accurate Mass

Fitch¹,

Tran²,

Young³

et al. 2009

DML

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“…104 Bottom center, an imiloxan metabolite. 105 Bottom right, a brimonidine metabolite. 106 The atoms of experimentally observed quinone forming pairs are circled.…”

Section: Figurementioning

confidence: 99%

Deep Learning to Predict the Formation of Quinone Species in Drug Metabolism

Hughes

Swamidass

2017

Chem. Res. Toxicol.

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Many adverse drug reactions are thought to be caused by electrophilically reactive drug metabolites that conjugate to nucleophilic sites within DNA and proteins, causing cancer or toxic immune responses. Quinone species, including quinone-imines, quinone-methides, and imine-methides, are electrophilic Michael acceptors that are often highly reactive and comprise over 40% of all known reactive metabolites. Quinone metabolites are created by cytochromes P450 and peroxidases. For example, cytochromes P450 oxidize acetaminophen to N-acetyl-p-benzoquinone imine, which is electrophilically reactive and covalently binds to nucleophilic sites within proteins. This reactive quinone metabolite elicits a toxic immune response when acetaminophen exceeds a safe dose. Using a deep learning approach, this study reports the first published method for predicting quinone formation: the formation of a quinone species by metabolic oxidation. We model both one- and two-step quinone formation, enabling accurate quinone formation predictions in nonobvious cases. We predict atom pairs that form quinones with an AUC accuracy of 97.6%, and we identify molecules that form quinones with 88.2% AUC. By modeling the formation of quinones, one of the most common types of reactive metabolites, our method provides a rapid screening tool for a key drug toxicity risk. The XenoSite quinone formation model is available at http://swami.wustl.edu/xenosite/p/quinone.

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“…Assessment of the potential to form covalent protein adducts with hepatic proteins was essentially performed as described previously elsewhere (Fitch et al, 2010). In brief, [ 14 C]-labeled basimglurant (49.2 mCi/mmol) was incubated with microsomal preparations, and radioactivity irreversibly bound to proteins after washing was measured.…”

Section: In Vitro Pharmacology and In Vitro Safetymentioning

confidence: 99%

Pharmacology of Basimglurant (RO4917523, RG7090), a Unique Metabotropic Glutamate Receptor 5 Negative Allosteric Modulator in Clinical Development for Depression

Lindemann

Porter

Scharf

et al. 2015

J Pharmacol Exp Ther

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Major depressive disorder (MDD) is a serious public health burden and a leading cause of disability. Its pharmacotherapy is currently limited to modulators of monoamine neurotransmitters and secondgeneration antipsychotics. Recently, glutamatergic approaches for the treatment of MDD have increasingly received attention, and preclinical research suggests that metabotropic glutamate receptor 5 (mGlu5) inhibitors have antidepressant-like properties. Basimglurant (2-chloro-4-[1-(4-fluoro-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridine) is a novel mGlu5 negative allosteric modulator currently in phase 2 clinical development for MDD and fragile X syndrome. Here, the comprehensive preclinical pharmacological profile of basimglurant is presented with a focus on its therapeutic potential for MDD and drug-like properties. Basimglurant is a potent, selective, and safe mGlu5 inhibitor with good oral bioavailability and long half-life supportive of once-daily administration, good brain penetration, and high in vivo potency. It has antidepressant properties that are corroborated by its functional magnetic imaging profile as well as anxiolytic-like and antinociceptive features. In electroencephalography recordings, basimglurant shows wakepromoting effects followed by increased delta power during subsequent non-rapid eye movement sleep. In microdialysis studies, basimglurant had no effect on monoamine transmitter levels in the frontal cortex or nucleus accumbens except for a moderate increase of accumbal dopamine, which is in line with its lack of pharmacological activity on monoamine reuptake transporters. These data taken together, basimglurant has favorable drug-like properties, a differentiated molecular mechanism of action, and antidepressant-like features that suggest the possibility of also addressing important comorbidities of MDD including anxiety and pain as well as daytime sleepiness and apathy or lethargy.

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Application of Modern Drug Metabolism Structure Determination Tools and Assays to the In Vitro Metabolism of Imiloxan

Cited by 8 publications

References 19 publications

Revisiting the Metabolism of Ketoconazole Using Accurate Mass

Revisiting the Metabolism of Ketoconazole Using Accurate Mass

Deep Learning to Predict the Formation of Quinone Species in Drug Metabolism

Pharmacology of Basimglurant (RO4917523, RG7090), a Unique Metabotropic Glutamate Receptor 5 Negative Allosteric Modulator in Clinical Development for Depression

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