In vitro Drug Metabolism Investigation of 7-Ethoxycoumarin in Human, Monkey, Dog and Rat Hepatocytes by High Resolution LC-MS/MS

Feng, Wan-Yong; Wen, Jenny; Stauber, Kathe

doi:10.2174/1872312812666180418142056

Cited by 6 publications

(4 citation statements)

References 27 publications

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“…The typical results of AUR metabolites in mice feces are provided in Figure 2a,b, but its metabolites could be detected only in the AUR treatment group (Figure 2c,e,g). Although the metabolism of ETC in vitro has been reported previously (Feng et al, 2018), a comprehensive profile of ETC metabolism in vivo and in vitro is presented here. Five metabolites and seven metabolites were detected by in vivo and in vitro metabolism of ETC, respectively (Table S1).…”

Section: Resultsmentioning

confidence: 90%

“…In the metabolism of ETC, the aldehyde metabolite Me3 was the characteristic product. As the intermediate metabolite, Me3 could metabolize to alcohol and carboxylic acid metabolites Me4 and Me5 (Feng et al, 2018). By contrast, in the metabolism of AUR, the aldehyde metabolite was not detected, and the alcohol and carboxylic acid products Ma2 and Ma3 were generated directly, instead of being formed by the aldehyde metabolite.…”

Section: Discussionmentioning

confidence: 99%

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Metabolomics reveals the role of isopentenyl group in coumarins metabolism

Zhao

Cheng

et al. 2021

Biomedical Chromatography

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Coumarins are a group of natural compounds commonly found in the families of Rutaceae and Umbelliferae. 7‐Isopentenyloxycoumarin (ISC), auraptene (AUR), and umbelliprenin (UM) belong to prenyloxycoumarins (PYCs), which link isopentenyl, geranyl, and farnesyl group at C7 position, respectively. The substituent of 7‐ethoxycoumarin (ETC) is the ethyl group. In this study, UPLC–ESI–QTOF–MS (ultra‐performance liquid chromatography–electrospray ionization–quadrupole time of flight–MS)‐based metabolomics was used to evaluate the in vivo and in vitro metabolism of PYCs. Results showed that ETC produced 10 known metabolites, and ISC was transformed into 17 metabolites in vivo and in vitro, which were undescribed compounds. A total of 35 AUR metabolites, including 34 undescribed metabolites were identified, and 21 metabolites were reported for the first time in UM. The results indicated that hydroxylation and N‐acetylcysteine conjugation were the common metabolic reactions for PYCs. The metabolic rates of ETC, ISC, AUR and UM were 26%, 36%, 81%, and 38%, respectively, in human liver microsome, while they were 24%, 40%, 80%, and 37%, respectively, in mouse liver microsomes. In addition, recombinant cytochrome P450s (CYPs) screening showed that CYP1A1, 2C19, 3A4, and 3A5 were the major metabolic enzymes involved in the formation of hydroxylation metabolites. Together, these results suggest that the isopentenyl group plays an important role in the metabolism of PYCs.

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Section: Resultsmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Metabolomics reveals the role of isopentenyl group in coumarins metabolism

Zhao

Cheng

et al. 2021

Biomedical Chromatography

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“…Expression of phase II enzymes in ICOs was generally higher than that of phase I enzymes. Notably, we observed relatively high expression of phase II enzymes in HL-ICOs compared to PHHs and HepaRGs, such as UGT2B11, UGT2B15, SULT1C2, and SULT1B1, suggesting differential activity in phase II metabolism pathways, as was observed by 7-hydroxycoumarin metabolite formation [ 42 ].…”

Section: Discussionmentioning

confidence: 99%

Drug Metabolism of Hepatocyte-like Organoids and Their Applicability in In Vitro Toxicity Testing

et al. 2023

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Emerging advances in the field of in vitro toxicity testing attempt to meet the need for reliable human-based safety assessment in drug development. Intrahepatic cholangiocyte organoids (ICOs) are described as a donor-derived in vitro model for disease modelling and regenerative medicine. Here, we explored the potential of hepatocyte-like ICOs (HL-ICOs) in in vitro toxicity testing by exploring the expression and activity of genes involved in drug metabolism, a key determinant in drug-induced toxicity, and the exposure of HL-ICOs to well-known hepatotoxicants. The current state of drug metabolism in HL-ICOs showed levels comparable to those of PHHs and HepaRGs for CYP3A4; however, other enzymes, such as CYP2B6 and CYP2D6, were expressed at lower levels. Additionally, EC50 values were determined in HL-ICOs for acetaminophen (24.0–26.8 mM), diclofenac (475.5–>500 µM), perhexiline (9.7–>31.5 µM), troglitazone (23.1–90.8 µM), and valproic acid (>10 mM). Exposure to the hepatotoxicants showed EC50s in HL-ICOs comparable to those in PHHs and HepaRGs; however, for acetaminophen exposure, HL-ICOs were less sensitive. Further elucidation of enzyme and transporter activity in drug metabolism in HL-ICOs and exposure to a more extensive compound set are needed to accurately define the potential of HL-ICOs in in vitro toxicity testing.

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“…All samples were stored at -70 ºC ± 10 ºC. The samples incubated with test item were then transferred (frozen on dry ice, at -80 ºC) to test site for characterization of parent substance and metabolites in the incubation medium by LC-MS/MS analysis [13]. The percentage of sample radioactivity associated with 7-EC and known metabolites, 7-hydroxycoumarin glucuronide (7-HCG), 7 hydroxycoumarin sulphate (7-HCS) and 7 hydroxycoumarin (7-HC) was determined for all samples…”

Section: Dose Formulation and Incubation With Pooled Rat Dog Monkey A...mentioning

confidence: 99%

Species differences metabolism in vitro model of a novel analgesic propoxazepam with polymodal mechanism of action

Yakovych¹,

Semenovich²,

Borysovych³

et al. 2022

GSC Biol. and Pharm. Sci.

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The aim of this study was to identify the Propoxazepam metabolites, formed by suspension of rat, dog, monkey and minipig cryopreserved hepatocytes. A suitable chromatographic method was developed for the profiling of Propoxazepam and its metabolites. Samples were analyzed using a Waters Vion high resolution LC-MS/MS instrument and data examined using Waters Unifi software to determine the identity of the most abundant metabolites. The reported proportions of parent compound and its metabolites assume equivalent mass spectrometer detector response. The proportions of unchanged parent drug after 4 hour incubation with hepatocytes varied between 37.1 to 96.0 % of the total peak response. The most abundant metabolite observed across all species was oxidised Propoxazepam (3-hydroxy derivative) which accounted for between 2.5 to 46.5 % of the total peak response in the 4 hour samples. Four other minor metabolites were observed each representing <10 % of the total peak response. The primary route of in vitro metabolism was by oxidation, dealkylation and conjugation with glucuronic acid. Some species differences were noted. The presented data indicate the absence of reactive chemicals among the metabolites of Propoxazepam. Propoxazepam underwent moderate metabolism in monkey cryopreserved hepatocytes after 4 hour incubation. Less extensive metabolism was observed in rat and minipig hepatocytes after the same incubation period and limited metabolism was observed in dog hepatocytes.

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In vitro Drug Metabolism Investigation of 7-Ethoxycoumarin in Human, Monkey, Dog and Rat Hepatocytes by High Resolution LC-MS/MS

Cited by 6 publications

References 27 publications

Metabolomics reveals the role of isopentenyl group in coumarins metabolism

Metabolomics reveals the role of isopentenyl group in coumarins metabolism

Drug Metabolism of Hepatocyte-like Organoids and Their Applicability in In Vitro Toxicity Testing

Species differences metabolism in vitro model of a novel analgesic propoxazepam with polymodal mechanism of action

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