A review of LC–MS techniques and high-throughput approaches used to investigate drug metabolism by cytochrome P450s

Youdim, Kuresh A.; Saunders, Kenneth

doi:10.1016/j.jchromb.2010.02.013

Cited by 58 publications

(36 citation statements)

References 95 publications

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“…Among the untargeted studies, metabolite profiling and metabolite identification (metabolite ID) have to be carried out with high-end MS devices (i.e., orbitrap or QqTOF/MS) for investigating the numerous unknown metabolites derived from metabolism [8,9]. Over the past few years, significant efforts have been made to improve the acquisition rate, sensitivity and resolving power of high-resolution MS instruments, which are generally employed for these more sophisticated in vitro metabolism studies [10][11][12]. The most recent developments of quadrupole-based instruments have been focused on making them more sensitive and user-friendly, and the most widely used strategy for simple in vitro metabolism assay consists in performing generic LC conditions combined with state-of the-art MS/MS detector, to achieve a sufficient level of sensitivity and selectivity.…”

Section: Introductionmentioning

confidence: 99%

Comparison of liquid chromatography and supercritical fluid chromatography coupled to compact single quadrupole mass spectrometer for targeted in vitro metabolism assay

Spaggiari

Mehl

Desfontaine

et al. 2014

Journal of Chromatography A

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Section: Introductionmentioning

confidence: 99%

Comparison of liquid chromatography and supercritical fluid chromatography coupled to compact single quadrupole mass spectrometer for targeted in vitro metabolism assay

Spaggiari

Mehl

Desfontaine

et al. 2014

Journal of Chromatography A

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“…Currently, to track the demanding throughput required for screening in drug discovery, pharmaceutical and biotechnology companies are applying automation and robotic technologies such as liquid handling systems. They are being used for multiple sample preparations to increase the number of molecules that can be biologically assayed (40–42). The RABiT is an example of an advanced throughput system developed at Columbia University Medical Center for the purpose of biological dosimetry applications (2, 5, 43, 44).…”

Section: Discussionmentioning

confidence: 99%

Development of a High-Throughput and Miniaturized Cytokinesis-Block Micronucleus Assay for Use as a Biological Dosimetry Population Triage Tool

et al. 2015

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Biodosimetry is an essential tool for providing timely assessments of radiation exposure. For a large mass-casualty event involving exposure to ionizing radiation, it is of utmost importance to rapidly provide dose information for medical treatment. The well-established cytokinesis-block micronucleus (CBMN) assay is a validated method for biodosimetry. However, the need for an accelerated sample processing is required for the CBMN assay to be a suitable population triage tool. We report here on the development of a high-throughput and miniaturized version of the CMBN assay for accelerated sample processing.

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“…Six of the CYPs, CYP1A2, CYP3A, CYP2C9, CYP2C19, CYP2D6, and CYP2E1, play a major role in drug metabolism [5] . Their probes have been widely used to evaluate the activities of the individual CYPs in the field of drug metabolism [6] . The cocktail approach involves the administration of multiple probes simultaneously and the measurement of the plasma kinetics of probes [7,8] , which is more convenient and saves costs and time compared with single-probe substrate studies [9][10][11][12] .…”

Section: Introductionmentioning

confidence: 99%

Chronic administration of caderofloxacin, a new fluoroquinolone, increases hepatic CYP2E1 expression and activity in rats

et al. 2016

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Aim: Caderofloxacin is a new fluoroquinolone that is under phase III clinical trials in China. Here we examined the effects of caderofloxacin on rat hepatic cytochrome P450 (CYP450) isoforms as well as the potential of caderofloxacin interacting with co-administered drugs. Methods: Male rats were treated with caderofloxacin (9 mg/kg, ig) once or twice daily for 14 consecutive days. The effects of caderofloxacin on CYP3A, 2D6, 2C19, 1A2, 2E1 and 2C9 were evaluated using a "cocktail" of 6 probes (midazolam, dextromethorphan, omeprazole, theophylline, chlorzoxazone and diclofenac) injected on d 0 (prior to caderofloxacin exposure) and d 15 (after caderofloxacin exposure). Hepatic microsomes from the caderofloxacin-treated rats were used to assess CYP2E1 activity and chlorzoxazone metabolism. The expression of CYP2E1 mRNA and protein in hepatic microsomes was analyzed with RT-PCR and Western blotting, respectively. Results: Fourteen-day administration of caderofloxacin significantly increased the activity of hepatic CYP2E1, leading to enhanced metabolism of chlorzoxazone. In vitro microsomal study confirmed that CYP2E1 was a major metabolic enzyme involved in chlorzoxazone metabolism, and the 14-d administration of caderofloxacin significantly increased the activity of CYP2E1 in hepatic microsomes, resulting in increased formation of 6-hydroxychlorzoxazone. Furthermore, the 14-d administration of caderofloxacin significantly increased the expression of CYP2E1 mRNA and protein in liver microsomes, which was consistent with the pharmacokinetic results. Conclusion: Fourteen-day administration of caderofloxacin can induce the expression and activity of hepatic CYP2E1 in rats. When caderofloxacin is administered, a potential drug-drug interaction mediated by CYP2E1 induction should be considered.

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A review of LC–MS techniques and high-throughput approaches used to investigate drug metabolism by cytochrome P450s

Cited by 58 publications

References 95 publications

Comparison of liquid chromatography and supercritical fluid chromatography coupled to compact single quadrupole mass spectrometer for targeted in vitro metabolism assay

Comparison of liquid chromatography and supercritical fluid chromatography coupled to compact single quadrupole mass spectrometer for targeted in vitro metabolism assay

Development of a High-Throughput and Miniaturized Cytokinesis-Block Micronucleus Assay for Use as a Biological Dosimetry Population Triage Tool

Chronic administration of caderofloxacin, a new fluoroquinolone, increases hepatic CYP2E1 expression and activity in rats

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