Application of substrate depletion assay to evaluation of CYP isoforms responsible for stereoselective metabolism of carvedilol

Iwaki, Masaya; Niwa, Toshiyuki; Saya, Bandoh; Itoh, Masashi; Hirose, Hitomi; Kawase, Atsushi; Kono, Hiroshi

doi:10.1016/j.dmpk.2016.08.007

Cited by 11 publications

(21 citation statements)

References 24 publications

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“…In our previous study, the quantitative contribution of different CYP isoforms to enantioselective CAR metabolism was evaluated using a substrate depletion assay in humans (Iwaki et al, 2016). The study results indicated that CYP2D6 shows the highest contribution to the metabolism of the R-enantiomer, followed by CYP3A4, CYP1A2, and CYP2C9, whereas the metabolism of the S-enantiomer is mainly mediated by CYP1A2, followed by CYP2D6 and CYP3A4 (Table 1).…”

Section: Discussionmentioning

confidence: 99%

“…1). b) Contribution in HLM (%) estimated by using recombinant human CYP was mentioned in our previous report (Iwaki et al, 2016 …”

Section: Depletion Of Car By Recombinant Cypsmentioning

confidence: 99%

“…The concentrations of R-and S-CAR were measured using an HPLC system (Liquid Chromatograph model LC-10AD; Shimadzu, Kyoto, Japan) equipped with a fluorescence detector (RF-10A), according to the method reported by Rathod et al (2007) with some modifications (Iwaki et al, 2016). Briefly, chromatographic separation was achieved using a Cosmosil 5C 18 -ARII column (4.6 × 150 mm, 5 μm, Nacalai Tesque, Kyoto, Japan) maintained at 40°C.…”

Section: Hplc Assay Of Carmentioning

confidence: 99%

“…For example, CYP2D6 which is highly polymorphic enzyme (> 100 allelic variants) are involved in CAR metabolism. Therefore, the present study aimed to clarify the CYP isoforms involving in R-CAR and S-CAR metabolism and to compare it to the previous results in human liver microsome (Iwaki et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

“…We recently demonstrated the quantitative characterization of the human CYP isoforms responsible for the stereoselective biotransformation of CAR by measuring the disappearance rate of parent compounds (Iwaki et al, 2016). In the preclinical development of new drugs, pharmacokinetic and metabolic profiles, and toxicological properties are determined in animals such as rats.…”

Section: Introductionmentioning

confidence: 99%

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Relative contribution of rat CYP isoforms responsible for stereoselective metabolism of carvedilol

et al. 2018

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-The relative contribution of cytochrome P450 (CYP) isoforms responsible for carvedilol (CAR) oxidation in rats were evaluated in order to compare with that of reported human CYPs responsible for the metabolism of CAR enantiomers. The depletion of CAR enantiomers by recombinant CYPs and the effects of CYP-selective inhibitors on the depletion catalyzed by rat liver microsomes (RLM) was determined. Quinine (rat CYP2D inhibitor) markedly inhibited the metabolism of both R-and S-CAR by RLM. The metabolism of S-CAR was inhibited more than that of R-CAR by furafylline, (a CYP1A2 inhibitor, 53.5% vs 11.3%), α-naphthoflavone (a CYP1A2 inhibitor, 64.5% vs 33.6%), and ketoconazole (a CYP3A inhibitor, 87.1% vs 51.2%). Among the CYPs examined, CYP2D2 showed the highest metabolic activities against both the enantiomers. R-CAR was mainly metabolized by CYP2D2 and CYP3A2. CYP2C11 and CYP3A1, in addition to CYP2D2 and CYP3A2 showed higher metabolic activities against S-CAR than that against R-CAR. These results suggest that CYP2D2 predominantly catalyzed R-CAR metabolism, whereas CYP2D2 and CYP3A1/2 catalyzed S-CAR metabolism in rats.

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Section: Discussionmentioning

confidence: 99%

“…1). b) Contribution in HLM (%) estimated by using recombinant human CYP was mentioned in our previous report (Iwaki et al, 2016 …”

Section: Depletion Of Car By Recombinant Cypsmentioning

confidence: 99%

Section: Hplc Assay Of Carmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Relative contribution of rat CYP isoforms responsible for stereoselective metabolism of carvedilol

et al. 2018

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Effect of Roux‐En‐Y Gastric Bypass in the Pharmacokinetics of (R)‐Carvedilol and (S)‐Carvedilol

Yamamoto

Cristofoletti

Vozmediano

et al. 2023

The Journal of Clinical Pharma

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Roux‐en‐Y gastric bypass is one of the most common surgical treatments for obesity due to the effective long‐term weight loss and remission of associated comorbidities. Carvedilol, a third‐generation β‐blocker, is prescribed to treat cardiovascular diseases. This drug is a weak base with low and pH‐dependent solubility and dissolution and high permeability. As the changes in the gastrointestinal tract anatomy and physiology after roux‐en‐Y gastric bypass can potentially affect drug pharmacokinetics, this study aimed to assess the effect of roux‐en‐Y gastric bypass on the pharmacokinetics of carvedilol enantiomers. Nonobese (n = 15, body mass index < 25 kg/m2), obese (n = 19, body mass index ≥ 30), and post‐roux‐en‐Y gastric bypass subjects submitted to surgery for at least 6 months (n = 19) were investigated. All subjects were administered a single oral dose of 25‐mg racemic carvedilol, and blood was sampled for up to 24 hours. Plasma concentrations of (R)‐ and (S)‐carvedilol were determined by liquid chromatography–tandem mass spectrometry. The maximum plasma concentration (Cmax) and the area under the plasma concentration‐time curve (AUC) of (R)‐carvedilol were 2‐ to 3‐fold higher than (S)‐carvedilol in all groups. Obese subjects have shown reduced Cmax of (R)‐ and (S)‐carvedilol without changing the AUC. Post‐roux‐en‐Y gastric bypass subjects presented a 3.5‐fold reduction in the Cmax of the active (S)‐carvedilol and a 1.9 reduction in the AUC from time 0 to infinity compared to nonobese subjects. The time to reach Cmax of (S)‐carvedilol increased 2.5‐fold in post‐roux‐en‐Y gastric bypass subjects compared to obese or nonobese. Although the β‐blockade response was not assessed, the reduced exposure to carvedilol in subjects post‐roux‐en‐Y gastric bypass may be clinically relevant and require dose adjustment.

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Transcriptomics and metabolomics reveal the role of CYP1A2 in psoralen/isopsoralen‐induced metabolic activation and hepatotoxicity

Zhang

Song

Zhao

et al. 2022

Phytotherapy Research

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Psoralen and isopsoralen are the pharmacologically important but hepatotoxic components in Psoraleae Fructus. The purpose of this study was to reveal the underlying mechanism of psoralen/isopsoralen‐induced hepatotoxicity. Initially, we applied integrated analyses of transcriptomic and metabolomic profiles in mice treated with psoralen and isopsoralen, highlighting the xenobiotic metabolism by cytochromes P450 as a potential pathway. Then, with verifications of expression levels by qRT‐PCR and western blot, affinities by molecular docking, and metabolic contributions by recombinant human CYP450 and mouse liver microsomes, CYP1A2 was screened out as the key metabolic enzyme. Afterwards, CYP1A2 induction and inhibition models in HepG2 cells and mice were established to verify the role of CYP1A2, demonstrating that induction of CYP1A2 aggravated the hepatotoxicity, and conversely inhibition alleviated the hepatotoxic effects. Additionally, we detected glutathione adducts with reactive intermediates of psoralen and isopsoralen generated by CYP1A2 metabolism in biosystems of recombinant human CYP1A2 and mouse liver microsomes, CYP1A2‐overexpressed HepG2 cells, mice livers and the chemical reaction system using UPLC‐Q‐TOF‐MS/MS. Ultimately, the high‐content screening presented the cellular oxidative stress and relevant hepatotoxicity due to glutathione depletion by reactive intermediates. In brief, our findings illustrated that CYP1A2‐mediated metabolic activation is responsible for the psoralen/isopsoralen‐induced hepatotoxicity.

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Application of substrate depletion assay to evaluation of CYP isoforms responsible for stereoselective metabolism of carvedilol

Cited by 11 publications

References 24 publications

Relative contribution of rat CYP isoforms responsible for stereoselective metabolism of carvedilol

Relative contribution of rat CYP isoforms responsible for stereoselective metabolism of carvedilol

Effect of Roux‐En‐Y Gastric Bypass in the Pharmacokinetics of (R)‐Carvedilol and (S)‐Carvedilol

Transcriptomics and metabolomics reveal the role of CYP1A2 in psoralen/isopsoralen‐induced metabolic activation and hepatotoxicity

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