Enantioselective Metabolism of Flufiprole in Rat and Human Liver Microsomes

Lin, Chunmian; Miao, Yelong; Qian, Mingrong; Wang, Qiang; Zhang, Hu

doi:10.1021/acs.jafc.5b05853

Cited by 19 publications

(9 citation statements)

References 28 publications

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“…These results demonstrated that the penetration process of the SC could not provide any enantiomer selectivity, which also has been illustrated by molecular simulation results, presented in Figure 3. Furthermore, as was shown might be attributed to the competitive elimination of enantiomers under the action of metabolizing enzyme in the body as previous reports (Lin et al, 2016).…”

Section: In Vivo Permeation Studysupporting

confidence: 73%

Chiral 4- O -acylterpineol as transdermal permeation enhancers: insights of the enhancement mechanisms of a transdermal enantioselective delivery system for flurbiprofen

Chu

Wang

et al. 2020

Drug Delivery

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In order to devise more effective penetration enhancers, 4-O-acylterpineol derivatives which were expected to be hydrolyzed into nontoxic metabolites by esterase in the living epidermis, were synthesized from 4-terpineol (4-TER) enantiomers and straight chain fatty acids. Their promoting activities on the SR-flurbiprofen and its enantiomers were tested across full-thickness rabbit skin, as well as to correlate under in vitro and in vivo conditions. The permeation studies indicated that both d-4-O-acylterpineol and l-4-O-acylterpineol had significant enhancing effects, interestingly, d-4-O-aclyterpineol had higher enhancing effects than l-4-O-aclyterpineol with the exception of d-4-methyl-1-(1-methylethyl)-3cyclohexen-1-yl octadec-9-enoate (d-4-T-dC18). The mechanism of 4-O-acylterpineol facilitating the drug penetration across the skin was confirmed by Attenuated total reflection-Fourier transformed infrared spectroscopy (ATR-FTIR) and molecular simulation. The mechanism of penetration enhancers promoting drug release was explored by the in vitro release experiment. Finally, a relative safety skin irritation of enhancers was also investigated by in vivo histological evaluation. The present research suggested that d-4-O-aclyterpineol and l-4-O-aclyterpineol could significantly promote the penetration of SR-flurbiprofen and its enantiomers both in vitro and in vivo, with the superiorities of high flux and low dermal toxicity.

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Section: In Vivo Permeation Studysupporting

confidence: 73%

Chiral 4- O -acylterpineol as transdermal permeation enhancers: insights of the enhancement mechanisms of a transdermal enantioselective delivery system for flurbiprofen

Chu

Wang

et al. 2020

Drug Delivery

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“…Competitive inhibition, transformation, and interaction between stereoisomers may lead to the generation of stereoselective metabolism in organisms. Lin et al 34 found that the metabolism of flufiprole within RLMs and HLMs has enantioselectivity. Zhan et al 35 presented that acetofenate was quickly metabolized to acetofenate-alcohol and the metabolic process was significantly enantioselective with preferential degradation of (−)-acetofenate and formation of (−)-acetofenate-alcohol in rabbit liver microsomes.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Enantioselective Metabolic Mechanism and Metabolism Pathway of Pydiflumetofen in Rat Liver Microsomes: In Vitro and In Silico Study

Wang

et al. 2022

J. Agric. Food Chem.

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Pydiflumetofen (PYD) has been used worldwide. However, the enantioselective fate of PYD within mammals is not clear. Thus, the enantioselective metabolism and its potential mechanisms of PYD were explored via in vitro and in silico. Consistent results were observed between metabolism and enzyme kinetics experiments, with S-PYD metabolizing faster than R-PYD in rat liver microsomes. Moreover, CYP3A1 and carboxylesterase 1 were found to be major enzymes participating in the metabolism of PYD. Based on the computational results, S-PYD bound with CYP3A1 and carboxylesterase 1 more tightly with lower binding free energy than R-PYD, explaining the mechanism of enantioselective metabolism. Nine phase I metabolites of PYD were identified, and metabolic pathways of PYD were speculated. This study is the first to clarify the metabolism of PYD in mammals, and further research to evaluate the toxicological implications of these metabolites will help in assessing the risk of PYD.

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“…On the contrary, the V max of S ‐(+)‐fipronil (447 ± 19 pmol/min/mg protein) in the human liver microsome was higher than that of R ‐(−)‐fipronil (300 ± 8 pmol/min/mg protein), and the CL int values were also not significantly different for the enantiomers (Carrao, Dos Reis Gomes, et al, 2019). Alternative enantioselective metabolism of flufiprole, another phenylprazole insecticide, in rat and human liver microsomes was observed, that is, selectively metabolized R ‐(−)‐fipronil in rat but S ‐(+)‐fipronil in human microsome (Lin et al, 2016). Different enantioselective metabolic behaviors observed in different organisms are likely due to the different compositions and contents of metabolizing enzymes among species (Arora et al, 2015; Narimatsu et al, 2000).…”

Section: Resultsmentioning

confidence: 99%

Identification of Cytochrome P450 Isozymes Involved in Enantioselective Metabolism of Fipronil in Fish Liver: In Vitro Metabolic Kinetics and Molecular Modeling

You

2021

Enviro Toxic and Chemistry

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Fipronil has been frequently detected in waterways worldwide at concentrations that threaten aquatic organisms, yet the metabolic behavior of fipronil enantiomers in aquatic organisms is largely unknown, which is of significance in enantioselective toxicity evaluation. We quantitatively identified the specific cytochrome P450 (CYP) isozymes involved in metabolizing fipronil enantiomers in tilapia by combining in vitro metabolic kinetic assays and molecular docking. Inhibition studies suggested that CYP1A enzyme was the main isoform catalyzing metabolism of fipronil and that CYP3A contributed in a limited way to the metabolism in fish liver S9. Both the dissipation rate constant and the maximum metabolic velocity of R-(−)-fipronil were greater than those of S-(+)-fipronil in tilapia liver S9, suggesting that tilapia selectively metabolized R-(−)-fipronil. The CYP1A1 isozyme exhibited the highest binding capacity to R-(−)-fipronil and S-(+)-fipronil (binding energy -9.39 and -9.17 kcal/mol, respectively), followed by CYP1A2 (-7.30 and -6.94 kcal/mol, respectively) and CYP3A4 (-7.16 and -6.91 kcal/mol, respectively). The results of in vitro metabolic assays and molecular docking were consistent, that is, CYP1A, specifically CYP1A1, exhibited a higher metabolic capacity to fipronil than CYP3A, and fish liver S9 selectively metabolized R-(−)-fipronil. The present study provides insight into the enantioselective metabolic behavior and toxicological implications of the in vitro metabolic kinetics of fipronil in fish.

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Enantioselective Metabolism of Flufiprole in Rat and Human Liver Microsomes

Cited by 19 publications

References 28 publications

Chiral 4- O -acylterpineol as transdermal permeation enhancers: insights of the enhancement mechanisms of a transdermal enantioselective delivery system for flurbiprofen

Chiral 4- O -acylterpineol as transdermal permeation enhancers: insights of the enhancement mechanisms of a transdermal enantioselective delivery system for flurbiprofen

Enantioselective Metabolic Mechanism and Metabolism Pathway of Pydiflumetofen in Rat Liver Microsomes: In Vitro and In Silico Study

Identification of Cytochrome P450 Isozymes Involved in Enantioselective Metabolism of Fipronil in Fish Liver: In Vitro Metabolic Kinetics and Molecular Modeling

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