scholarly journals Detoxification of the tricyclic antidepressant opipramol and its analog – IS-noh by UGT enzymes before and after activation by phase I enzymes in rat liver microsomes

2021 ◽  
Author(s):  
Anna Mieszkowska ◽  
Koleta Hemine ◽  
Anna Skwierawska ◽  
Ewa Augustin ◽  
Zofia Mazerska
Keyword(s):  
Phase I ◽  
Rat Liver ◽  
Phase Ii ◽  
Oxidation Product ◽  
Liver Microsomes ◽  
Correct Selection ◽  
Rat Liver Microsomes ◽  
Recombinant Enzymes ◽  
Data Set ◽  
Phase I Enzymes

AbstractThe present studies were carried out to evaluate the simultaneous one-pot metabolism of opipramol (IS-opi) and analog (IS-noh) by phase I and phase II enzymes present in rat liver microsomes (RLM) as an alternative to separate testing with recombinant enzymes. This approach allows for more time-saving and cost-effective screening of the metabolism of newly discovered drugs. We also considered that the lack of results for phase II, including UGT, often creates problems in correct selection of valuable compounds. Moreover, microsomes data set is richer in the contest and provides medical scientist to determine also the susceptibility of drugs to undergo phase I and then phase II. In the present work, we have shown that IS-noh was metabolized in vitro by phase I enzymes to the oxidation product, which was next transformed with UGTs to glucuronide. The results showed also that the previously known oxidation product of opipramol was changed to previously no reported glucuronidation product by UDP-glucuronosyltransferases. In addition, unlike IS-noh, opipramol did not prove to be the substrate for UGTs. Therefore, tricyclic antidepressants depending on the structure can trigger a different response after contact with UGT enzymes. Some will metabolize directly with UGTs, others only after activation by phase I enzymes.

In Vitro Metabolism of E2, G2: Novel Bile Acid-Coupling Camptothecin Analogues, in Rat Liver Microsomes

2021 ◽  
Vol 16 ◽  
Author(s):  
Xiangli Zhang ◽  
Qin Shen ◽  
Yi Wang ◽  
Leilei Zhou ◽  
Qi Weng ◽  
...  
Keyword(s):  
Bile Acid ◽  
Phase I ◽  
Rat Liver ◽  
Deoxycholic Acid ◽  
Liver Microsomes ◽  
Intrinsic Clearance ◽  
Rat Liver Microsomes ◽  
Camptothecin Analogues

Background: E2 (Camptothecin - 20 (S) - O- glycine - deoxycholic acid), and G2 (Camptothecin - 20 (S) - O - acetate - deoxycholic acid) are two novel bile acid-derived camptothecin analogues by introducing deoxycholic acid in 20-position of CPT(camptothecin) with greater anticancer activity and lower systematic toxicity in vivo. Objective: We aimed to investigate the metabolism of E2 and G2 by Rat Liver Microsomes (RLM). Methods: Phase Ⅰ and Phase Ⅱ metabolism of E2 and G2 in rat liver microsomes were performed respectively, and the mixed incubation of phase I and phase Ⅱ metabolism of E2 and G2 was also processed. Metabolites were identified by liquid chromatographic/mass spectrometry. Results: The results showed that phase I metabolism was the major biotransformation route for both E2 and G2. The isoenzyme involved in their metabolism had some difference. The intrinsic clearance of G2 was 174.7mL/min. mg protein, more than three times of that of E2 (51.3 mL/min . mg protein), indicating a greater metabolism stability of E2. 10 metabolites of E2 and 14 metabolites of G2 were detected, including phase I metabolites (mainly via hydroxylations and hydrolysis) and their further glucuronidation products. Conclusion: These findings suggested that E2 and G2 have similar biotransformation pathways except some difference in the hydrolysis ability of the ester bond and amino bond from the parent compounds, which may result in the diversity of their metabolism stability and responsible CYPs(Cytochrome P450 proteins).

scholarly journals Effects of Paederia foetida and its Bioactive Phytochemical Constituent Lupeol on Hepatic Phase I Drug Metabolism

2017 ◽  
Vol 12 (9) ◽  
pp. 1934578X1701200
Author(s):  
Sourabh Dubey ◽  
Kuntal Mitra ◽  
Bijoy Kumar De ◽  
Arijit Mondal ◽  
Anupam Bishayee
Keyword(s):  
Drug Interactions ◽  
Phase I ◽  
Rat Liver ◽  
Antioxidant Activities ◽  
Liver Microsomes ◽  
Ethanolic Extract ◽  
Rat Liver Microsomes ◽  
Paederia Foetida ◽  
Inhibitory Potential ◽  
Bioactive Constituent

There are many possible complications associated with the concomitant use of herbs and medications, but limited information is available on herb-herb or herb-drug interactions. Paederia foetida Linn. (family: Rubiaceae) is utilized in the Indian traditional medicine. It exhibits various pharmacological properties, such as antidiabetic, analgesic, anti-inflammatory, antimicrobial, hepatoprotective, anthelmintic, antiulcer and antioxidant activities. The purpose of the present work was to investigate the inhibitory potential of the P. foetida ethanolic extract and its bioactive constituent lupeol on hepatic phase I drug metabolizing enzymes. The high performance thin layer chromatography was performed for qualitative analysis of various extracts of P. foetida. The effects of P. foetida extract on rat liver microsomes (RLMs) and individual cytochrome P-450 (CYP) isozymes (CYP3A4 and CYP2D6) were investigated using CYP450-carbon monoxide complex assay and fluorescence microplate assay, respectively. The ethanolic extract and lupeol (both at a concentration of 100 μg/mL) showed 45±3.3 and 44±3.8% inhibition of rat liver microsomes, respectively, which were significantly less than that of known inhibitor ketoconazole (74±5.4% inhibition at 100 μg/mL). The 50% inhibitory concentrations (IC50) of ethanolic extract on CYP3A4 and CYP2D6 were 78±2.3 and 82±3.1 μg/mL, respectively, whereas its major bioactive constituent lupeol has IC50 values of 83±2.0 and 84±2.6 μg/mL for CYP3A4 and CYP2D6, respectively. The results were of lesser magnitude compared to known inhibitors, ketoconazole and quinidine, respectively. The current study revealed that P. foetida has less inhibitory potential in comparison to that of known inhibitors, ketoconazole and quinidine, on two major drug metabolizing isozymes, CYP3A4 and CYP2D6. Thus, the use of P. foetida as a complementary or alternative medicine may be safe in regard to herb-drug interactions.

Identification of cytochrome P450s involved in the metabolism of 6-benzyl-1-benzyloxymethyl-5-iodouracil (W-1) using human recombinant enzymes and rat liver microsomes in vitro

Xenobiotica ◽  
2017 ◽  
Vol 47 (8) ◽  
pp. 667-672 ◽  
Author(s):  
Ying-Yuan Lu ◽  
Hai-Xu Cheng ◽  
Xin Wang ◽  
Xiao-Wei Wang ◽  
Jun-Yi Liu ◽  
...  
Keyword(s):  
Rat Liver ◽  
Liver Microsomes ◽  
Cytochrome P450s ◽  
Rat Liver Microsomes ◽  
Recombinant Enzymes

Metabolic Analysis of Triptolide Microspheres in Human, Dog, Rabbit and Rat Liver Microsomes with UPLC-MS/MS Method

2020 ◽  
Vol 17 ◽  
Author(s):  
LiJuan Wang ◽  
Yan Liu ◽  
Rui Li ◽  
DongXian He
Keyword(s):  
Rat Liver ◽  
Liver Microsomes ◽  
Internal Standard ◽  
Gradient Elution ◽  
Rat Liver Microsomes ◽  
Good Precision ◽  
Kinetics Parameters ◽  
Measure Concentration ◽  
Standard Curve ◽  
Variation Of Parameters

Objectives: Triptolide (TPL) has been shown to have a good clinical effect on rheumatoid arthritis (RA). We designed TPL microspheres (TPL-MS) and investigated its metabolic behavior in human, dog, rabbit and rat liver microsomes (HLM, DLM, RLM and SDRLM) with UPLC-MS/MS method. Methods: First, a UPLC-MS/MS method was established to measure concentration of TPL in samples. The sample was separated on a C18 column (2.1×100 mm, 1.8μm) and eluted with a gradient elution. The precursor ion/product ion were m/z 378.1/361.0 for TPL and 260.0/116.2 for the internal standard. Then T1/2, Vmax and CLint were calculated from the above data. Finally, the metabolites of TPL-MS were identified by high-resolution UPLC-MS/MS. The sample was separated on a C18 column (2.1×100 mm, 2.2 μm) and eluted with isocratic elution. Mass spectrometric detection was carried out on a thermo Q-exactive mass spectrometer with HESI. The scanning range of precursor ions was from m/z 50 to m/z 750. Result and Discussion: Through several indicators including standard curve, precision, accuracy, stability, matrix effect and recovery rate, the enzymatic kinetics parameters including T1/2, Vmax and CLint were completed. Several metabolites of TPL-MS were identified. Conclusion: UPLC-MS/MS method is an accurate and sensitive method for determination of TPL in liver microsome samples with good precision, accuracy and stability. The variation of parameters indicated that the microspheres can delay the elimination of TPL in liver microsomes. The metabolism of TPL-MS varied among species, but no new metabolites appeared.

scholarly journals The metabolism of gelsevirine in human, pig, goat and rat liver microsomes

2021 ◽  
Author(s):  
Hua‐Hai Zhang ◽  
Wen‐Jia Yang ◽  
Ya‐Jun Huang ◽  
Wen‐Jing Li ◽  
Shuo‐Xin Zhang ◽  
...  
Keyword(s):  
Rat Liver ◽  
Liver Microsomes ◽  
Rat Liver Microsomes

scholarly journals A Unique Ribonucleic Acid of Low Molecular Weight from Rat Liver Microsomes

1968 ◽  
Vol 243 (1) ◽  
pp. 10-19
Author(s):  
J.A.A. Gardner ◽  
Mahlon B. Hoagland
Keyword(s):  
Molecular Weight ◽  
Rat Liver ◽  
Ribonucleic Acid ◽  
Liver Microsomes ◽  
Low Molecular Weight ◽  
Rat Liver Microsomes

scholarly journals Oxidation of docosahexaenoic acid by rat liver microsomes.

1984 ◽  
Vol 259 (9) ◽  
pp. 5776-5783 ◽  
Author(s):  
M VanRollins ◽  
R C Baker ◽  
H W Sprecher ◽  
R C Murphy
Keyword(s):  
Docosahexaenoic Acid ◽  
Rat Liver ◽  
Liver Microsomes ◽  
Rat Liver Microsomes
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