Metabolism of dictamnine in liver microsomes from mouse, rat, dog, monkey, and human

Wang, Pei; Zhao, Yunli; Zhu, Yingdong; Sun, Jianbo; Yerke, Aaron; Sang, Shengmin

doi:10.1016/j.jpba.2015.11.016

Cited by 35 publications

(25 citation statements)

References 17 publications

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“…The sheath gas was applied at a flow rate of 35 arbitrary units, and the auxiliary nitrogen gas was set at a flow rate of 10 arbitrary units. MS 2 and MS 3 data of the metabolites were obtained by selecting the (potential) precursor [M] + ions . Internal calibration by infusion of a calibrant achieved typical mass accuracy within 5 ppm.…”

Section: Methodsmentioning

confidence: 99%

Metabolic profile of Rhizoma coptidis in human plasma determined using ultra‐high‐performance liquid chromatography coupled with high‐resolution mass spectrometry

Zhang

Wang

Han

et al. 2017

Rapid Comm Mass Spectrometry

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Rationale: Rhizoma coptidis extract and its alkaloids show various pharmacological activities, but its metabolic profile in human plasma has not been thoroughly investigated. In the present research, the metabolism of Rhizoma coptidis at a clinical dose (5 g/60 kg/day) was systematically analyzed to determine its biotransformation processes in human plasma.Methods: In this research, the metabolites of Rhizoma coptidis in human plasma after oral administration of Rhizoma coptidis extract at a clinical dose were investigated using ultrahigh-performance liquid chromatography (UHPLC) coupled with high-resolution LTQ-Orbitrap mass spectrometry. The structural elucidation of the constituents was confirmed by comparing their retention times (t R ) and MS n fragments with those of standards and literature reports.Results: In total, two prototypes and twelve metabolites were detected in human plasma. The two prototypes were confidently identified using reference standards. Of the compounds detected, M7 (berberrubinen-9-O-glucuronide) was the most abundant based on its peak area, which indicates that this compound might be a pharmacokinetic marker for Rhizoma coptidis alkaloids in humans. Based on the metabolites detected in human plasma, a possible metabolic pathway for Rhizoma coptidis in vivo was proposed. Conclusions:The results indicated that the alkaloids in Rhizoma coptidis were extensively biotransformed in vivo mainly via conjugation with glucuronic acid (GluA) or sulfuric acid (SulA) to form phase II metabolites, and the GluA metabolites are likely the dominant form in human plasma. To the best of our knowledge, this is the first in vivo evaluation of the metabolic profile of the whole Rhizoma coptidis extract in human plasma, which is essential for determining the chemicals responsible for the pharmacological activities of Rhizoma coptidis in vivo. Moreover, it would be beneficial for us to further systematically study the pharmacokinetic behavior of Rhizoma coptidis in humans.

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Section: Methodsmentioning

confidence: 99%

Metabolic profile of Rhizoma coptidis in human plasma determined using ultra‐high‐performance liquid chromatography coupled with high‐resolution mass spectrometry

Zhang

Wang

Han

et al. 2017

Rapid Comm Mass Spectrometry

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“…42 Synthetic cannabinoid metabolism in human liver microsome HLM is the most common in vitro model due to low cost, availability, and simplicity of use, providing a rapid means to predict a SC's metabolic profile. 42,53 Hepatocytes offer a more similar metabolic environment to the physiology of the liver than HLM, although there are some limitations. The major advantage of hepatocytes compared to HLM is that the intact liver cells produce both phase I and phase II metabolites and in the appropriate abundances, whereas HLM may produce the spectrum of metabolites but the abundance of metabolites may not be reflective of the prevalence in authentic liver cells.…”

Section: Analytical Methods For Synthetic Cannabinoid Detectionmentioning

confidence: 99%

“…HLM is the most common in vitro model due to low cost, availability, and simplicity of use, providing a rapid means to predict a SC's metabolic profile . Hepatocytes offer a more similar metabolic environment to the physiology of the liver than HLM, although there are some limitations.…”

Section: What Are Synthetic Cannabinoids?mentioning

confidence: 99%

Approaches, Challenges, and Advances in Metabolism of New Synthetic Cannabinoids and Identification of Optimal Urinary Marker Metabolites

Diao

Huestis

2016

Clin Pharma and Therapeutics

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We review approaches for determining metabolism of new synthetic cannabinoids (SCs), and challenges and advances in identifying optimal urinary marker metabolites of SC intake. Metabolic patterns of different SC generations are evaluated, and a practical strategy offered for selecting SC urinary marker metabolites. Novel SCs are incubated with human hepatocytes, the most abundant and characteristic metabolites are identified with high-resolution mass spectrometry, and proposed hepatocyte marker metabolites are confirmed in authentic positive urine samples.

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“…Metabolic stability of NM-2201 was evaluated in HLM suspensions with slight modification with previous descriptions [28, 29]. In brief, the HLM incubation mixture contained 50 mM potassium phosphate buffer (pH 7.4), NADPH regenerating system (glucose-6-phosphate, MgCl 2 , and glucose-6-phosphate dehydrogenase), and 1 μM NM-2201.…”

Section: Methodsmentioning

confidence: 99%

In vitro and in vivo human metabolism of a new synthetic cannabinoid NM-2201 (CBL-2201)

et al. 2016

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In 2014, NM-2201 (CBL-2201), a novel synthetic cannabinoid (SC), was detected by Russian and United States laboratories. It was already added to the scheduled drugs list in Japan, Sweden and Germany. Unfortunately, no human metabolism data are currently available, making it challenging to confirm its intake because all previous investigated SCs were extensively metabolized. The present study aims to recommend appropriate marker metabolites by investigating NM-2201 metabolism in human hepatocytes and confirm the results in authentic human urine specimens. For the metabolic stability assay, 1 μM NM-2201 was incubated in human liver microsomes (HLMs) for up to 1 h; for metabolite profiling, 10 μM of NM-2201 was incubated in human hepatocytes for 3 h. Two authentic urine specimens from NM-2201 positive cases were analyzed after β-glucuronidase hydrolysis. Metabolite identification in hepatocyte samples and urine specimens was achieved with high-resolution mass spectrometry via information-dependent acquisition. NM-2201 was quickly metabolized in HLMs with an 8.0 min half-life. In human hepatocyte incubation samples, a total of thirteen NM-2201 metabolites were identified, generated mainly from ester hydrolysis and further hydroxylation, oxidative defluorination and subsequent glucuronidation. M13 (5-fluoro PB-22 3-carboxyindole) was the major metabolite. In the urine specimens, the parent drug NM-2201 was not detected; M13 was the predominant metabolite after β-glucuronidase hydrolysis. Therefore, based on our study, we recommend the M13 as a suitable urinary marker metabolite for confirming NM-2201 and/or 5F-PB-22 intake.

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Metabolism of dictamnine in liver microsomes from mouse, rat, dog, monkey, and human

Cited by 35 publications

References 17 publications

Metabolic profile of Rhizoma coptidis in human plasma determined using ultra‐high‐performance liquid chromatography coupled with high‐resolution mass spectrometry

Metabolic profile of Rhizoma coptidis in human plasma determined using ultra‐high‐performance liquid chromatography coupled with high‐resolution mass spectrometry

Approaches, Challenges, and Advances in Metabolism of New Synthetic Cannabinoids and Identification of Optimal Urinary Marker Metabolites

In vitro and in vivo human metabolism of a new synthetic cannabinoid NM-2201 (CBL-2201)

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