scholarly journals In-vitro assessment of CYP3A4 and CYPC29 inhibition potential of Lupeol using human liver microsomes

2019 ◽  
Vol 9 (2) ◽  
pp. 231-236
Author(s):  
LAXMAN DATTU KHATAL ◽  
Harinath More
Keyword(s):  
Drug Interactions ◽  
Human Liver ◽  
Biological Activities ◽  
Liver Microsomes ◽  
Inhibitory Effect ◽  
Positive Control ◽  
Human Liver Microsomes ◽  
Metabolite Formation ◽  
Physiological Concentration

Background: Lupeol is a dietary triterpene, possesses numerous biological activities. Lupeol is currently under development for chemotherapy and chemoprevention. The aim of present study was to determine the potential inhibitory effect of Lupeol on cytochrome P450 (CYP3A4 and CYP2C9 isozymes) activities in human liver microsomes (HLM). Methods:  The inhibition studies were conducted using testosterone 6β-hydroxylase (CYP3A4), and diclofenac 4’-Hydroxylase (CYP2C9) activity assay using positive control Ketoconazole and Sulphaphenazole, respectively. Inhibition study was performed by incubating lupeol (0 to 20 μM) with human liver microsomes, and the metabolite formation was analyzed by liquid chromatography-Tandem Mass Spectrometry (LC-MS/MS). Results: Luepol did not inhibit CYP3A4 and CYP2C9 isozymes mediated activities in human liver microsomes up to a maximum tested concentration of 20µM based on solubility under tested invitro conditions. Conclusions: Lupeol is not an inhibitor of the CYP3A4 and CYP2C9 isozymes. IC50 is greater than highest tested concentration as well as physiological concentration, where effect was measured with confidence. Therefore, clinically relevant pharmacokinetic herb-drug interactions are unlikely to occur between Lupeol and co-administered substrates of these CYP isozymes. Looking at the spectrum of biological activities and CYP inhibition potential of Lupeol; Lupeol can be used as adjuvant/ chemotherapy agent/ chemopreventive agent in therapy. Keywords: Lupeol, HLM, CYP3A4 and CYP2C9, Inhibition, herb–drug interactions

In-Vitro CYP3A4, CYP2E1 and UGT Activity in Human Liver Microsomes by Strobilanthes crispus Leaf Extracts

2020 ◽  
Vol 10 (2) ◽  
pp. 104-112
Author(s):  
Gabriel Akyirem Akowuah ◽  
Jin Han Chin ◽  
Siew Wei Yeong ◽  
Suk Yen Quah ◽  
Mariam Ahmad
Keyword(s):  
Drug Interactions ◽  
Human Liver ◽  
Liver Microsomes ◽  
Significant Inhibition ◽  
Human Liver Microsomes ◽  
Cyp3a4 Activity ◽  
Leaf Extracts ◽  
Strobilanthes Crispus ◽  
Glucuronosyl Transferase

Background: Strobilanthes crispus (L.) Bremek (Acanthaceae) leaves are used traditionally in Malaysia, Thailand, and Indonesia for anti-diabetic, anti-lytic, diuretic, and laxative purposes. Herb-drug interactions may potentiate or antagonize the absorption and metabolism of drugs which may result in potential toxicity. The aim of the present study was to investigate the effect of juice, hot aqueous, cold aqueous and methanol extracts of S. crispus leaves on phase I cytochrome 3A4 (CYP3A4) and Cytochrome 2E1 (CYP2E1) and phase II human liver enzyme UDP-Glucuronosyl Transferase (UGT). Methods: The herb-drug interactions of the leaf extracts and juice were determined by specific enzyme activity of CYP isoforms with specific probe substrate using spectrophotometry. CYP3A4 activity was measured for aminopyrine specific metabolite (formaldehyde) at 415 nm. CYP2E1 activity was determined using p-nitrophenol specific metabolite (p-nitrocatechol) at 535 nm. UGT activity was quantified through the consumption of p-nitrophenol by UGT at 405 nm. Results: All the S. crispus preparations showed significant inhibition of CYP3A4 activity. Only the methanolic extract showed a significant inhibition in CYP2E1. All the S. crispus extracts showed a significant effect on UGT activation at the higher concentration (1000 ng/ml). Only the cold aqueous extract and the juice showed UGT inhibition at lower concentration (1 ng/ml). Conclusion: S. crispus preparations showed in-vitro drug-herb interaction effects on human liver microsomes. Therefore, there is a possibility of drug-herb interaction could occur with S. crispus leaves through its effect on CYP3A4. Inhibition of the herb extracts on CYP2E1 could show anticarcinogenesis effects. The potency of drugs that metabolized via UGT pathway may be affected when co-administered with S. crispus leaf preparations.

Herb-Drug Interaction of 50 Chinese Herbal Medicines on CYP3A4 Activity in Vitro and in Vivo

2012 ◽  
Vol 40 (01) ◽  
pp. 57-73 ◽  
Author(s):  
Li-Heng Pao ◽  
Oliver Yoa-Pu Hu ◽  
Hsien-Yuan Fan ◽  
Chang-Ching Lin ◽  
Liang-Chun Liu ◽  
...  
Keyword(s):  
Enzymatic Activity ◽  
Drug Interactions ◽  
Human Liver ◽  
Liver Microsomes ◽  
Herbal Medicines ◽  
Human Liver Microsomes ◽  
Chinese Herbal Medicines ◽  
Chinese Herbal

The purpose of this study is to evaluate the effects of Chinese herbal medicines on the enzymatic activity of CYP3A4 and the possible metabolism-based herb-drug interactions in human liver microsomes and in rats. Fifty single-herbal preparations were screened for the activity of CYP3A4 using human liver microsomes for an in vitro probe reaction study. The enzymatic activity of CYP3A4 was estimated by determing the 6β-hydroxytestosterone metabolized from testosterone performed on a liquid chromatography-tandem mass spectrometry (LC-MS/MS). Huang Qin (Scutellaria baicalensis Geprgi), Mu Dan Pi (Paeonia suffruticosa Andr.), Ji Shiee Terng (Spatholobus suberectus Dunn.) and Huang Qi (Astragalus membranaceus [Fisch] Bge) have been demonstrated to have remarkable inhibiting effects on the metabolism of CYP3A4, whereas Xi Yi Hua (Magnolia biondii Pamp.) exhibited a moderate inhibition. These five single herbs were further investigated in an animal study using midazolam. Mu Dan Pi, Ji Shiee Terng and Huang Qi were observed to have greatly increased in the C max and AUC of midazolam. This study provides evidence of possible herb-drug interactions involved with certain single herbs.

scholarly journals Effects of DU-6859a, a New Quinolone Antimicrobial, on Theophylline Metabolism in In Vitro and In Vivo Studies

1998 ◽  
Vol 42 (7) ◽  
pp. 1751-1755 ◽  
Author(s):  
Yoshihito Niki ◽  
Kenichi Itokawa ◽  
Osamu Okazaki
Keyword(s):  
Healthy Subjects ◽  
Human Liver ◽  
Liver Microsomes ◽  
Urinary Metabolites ◽  
Inhibitory Effect ◽  
In Vivo Studies ◽  
Metabolite Formation ◽  
Theophylline Metabolism

ABSTRACT In vitro and in vivo studies were conducted to investigate the drug interaction between a new quinolone antimicrobial, DU-6859a, and theophylline (TP). The effect of DU-6859a on TP metabolism was evaluated in vitro by measuring the rate of TP metabolite formation by using human liver microsomes. DU-6859a inhibited the metabolism of TP, especially the formation of 1-methylxanthine, in vitro, but to a lesser extent than other drugs that are known to interact with TP. TP was administered alone (200 mg twice a day [b.i.d.] for 9 days) or in combination with DU-6859a (50 or 100 mg b.i.d. for 5 days) to six healthy subjects. DU-6859a administered at a dose of 50 mg resulted in no changes in serum TP concentrations, and slight increases in serum TP concentrations were observed at a dose of 100 mg. Moreover, the administration of 100 mg of DU-6859a resulted in decreases in all urinary TP metabolites, with significant differences. It appears that although DU-6859a has a weak inhibitory effect on TP metabolism in vitro, its concomitant use with TP at clinical dosage levels does not cause any adverse effects, showing only a slight increase in blood TP concentrations and a decrease in urinary metabolites.

In vitro drug-drug interactions with perospirone and concomitantly administered drugs in human liver microsomes

2003 ◽  
Vol 28 (1) ◽  
pp. 67-72 ◽  
Author(s):  
Jin Shimakura ◽  
Naoko Tani ◽  
Yoshiko Mizuno ◽  
Setsuko Komuro ◽  
Hiroshi Kanamaru
Keyword(s):  
Drug Interactions ◽  
Human Liver ◽  
Liver Microsomes ◽  
Human Liver Microsomes

scholarly journals Human Biotransformation of the Nonnucleoside Reverse Transcriptase Inhibitor Rilpivirine and a Cross-Species Metabolism Comparison

2013 ◽  
Vol 57 (10) ◽  
pp. 5067-5079 ◽  
Author(s):  
Julie M. Lade ◽  
Lindsay B. Avery ◽  
Namandjé N. Bumpus
Keyword(s):  
Reverse Transcriptase ◽  
Human Liver ◽  
Liver Microsomes ◽  
Transcriptase Inhibitor ◽  
Human Liver Microsomes ◽  
Metabolite Formation ◽  
Nonnucleoside Reverse Transcriptase Inhibitor ◽  
Reverse Transcriptase Inhibitor

ABSTRACTRilpivirine is a nonnucleoside reverse transcriptase inhibitor used to treat HIV-1. In the present study, the pathways responsible for the biotransformation of rilpivirine were defined. Using human liver microsomes, the formation of two mono- and two dioxygenated metabolites were detected via ultra high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). Mass spectral analysis of the products suggested that these metabolites resulted from oxygenation of the 2,6-dimethylphenyl ring and methyl groups of rilpivirine. Chemical inhibition studies and cDNA-expressed cytochrome P450 (CYP) assays indicated that oxygenations were catalyzed primarily by CYP3A4 and CYP3A5. Glucuronide conjugates of rilpivirine and a monomethylhydroxylated metabolite of rilpivirine were also detected and were found to be formed by UDP-glucuronosyltransferases (UGTs) UGT1A4 and UGT1A1, respectively. All metabolites that were identifiedin vitrowere detectablein vivo. Further, targeted UHPLC-MS/MS-basedin vivometabolomics screening revealed that rilpivirine treatment versus efavirenz treatment may result in differential levels of endogenous metabolites, including tyrosine, homocysteine, and adenosine. Rilpivirine biotransformation was also assessed across species using liver microsomes isolated from a range of mammals, and the metabolite profile identified using human liver microsomes was largely conserved for both oxidative and glucuronide metabolite formation. These studies provide novel insight into the metabolism of rilpivirine and the potential differential effects of rilpivirine- and efavirenz-containing antiretroviral regimens on the endogenous metabolome.

scholarly journals In vitro glucuronidation of trans-Piceid and trans-Piceatannol by human liver microsomes

OENO One ◽  
2008 ◽  
Vol 42 (4) ◽  
pp. 241
Author(s):  
Caroline Henry-Vitrac ◽  
Thomas Richard ◽  
Alexis Desmoulière ◽  
Jean-Pierre Monti ◽  
Jean-Michel Mérillon ◽  
...  
Keyword(s):  
Human Liver ◽  
Red Wine ◽  
Biological Activities ◽  
Liver Microsomes ◽  
Human Liver Microsomes ◽  
Beneficial Effects ◽  
Naturally Occurring ◽  
Phenolic Substances ◽  
First Time

<p style="text-align: justify;"><strong>Aims</strong> : The aim of the present investigation was to establish glucuronidation of trans-resveratrol derivates in the liver. Stilbenes are naturally occurring polyphenolic compounds which have been reported to have potential preventive activities in human diseases. Trans-stilbenes, mainly found in grapes and red wine, are important in terms of biological activities. However, little is known about the metabolism of these compounds in human.</p><p style="text-align: justify;"><strong>Methods and results</strong> : The glucuronoconjugation of stilbenes was investigated using human liver microsomes and the structure of new metabolites was characterized by LC-MS and proton NMR. For the first time, the structure of the metabolites of trans-piceid and trans-piceatannol was established. The reaction led to the formation of two glucuronides for trans-piceid and three for trans-piceatannol.</p><p style="text-align: justify;"><strong>Significance and impact of study</strong>: This study is of particular relevance since the phenolic substances of red wine (especially stilbenes) might be responsible for the potential beneficial effects of moderate and regular wine consumption.</p>

scholarly journals Metabolic Interaction of the Active Constituents ofCoptis chinensisin Human Liver Microsomes

2015 ◽  
Vol 2015 ◽  
pp. 1-5 ◽  
Author(s):  
Songcan Liu ◽  
Xinfeng Zhang ◽  
Furong Qiu ◽  
Ping Miao ◽  
Shujiao Shen ◽  
...  
Keyword(s):  
Chinese Medicine ◽  
Human Liver ◽  
Liver Microsomes ◽  
Inhibitory Effect ◽  
Human Liver Microsomes ◽  
Coptis Chinensis ◽  
Active Constituents ◽  
Metabolic Interaction ◽  
Inhibition Experiment

Coptis chinensisis commonly used in traditional Chinese medicine. The study investigated metabolic interaction of the active constituents (berberine, coptisine, palmatine, and jatrorrhizine) ofCoptis chinensisin human liver microsomes. After incubation of the four constituents ofCoptis chinensisin HLMs, the metabolism of the four constituents was observed by HPLC. Thein vitroinhibition experiment between the active constituents was conducted, and IC50value was estimated. Coptisine exhibited inhibitions against the formation of the two metabolites of berberine with IC50values of 6.5 and 8.3 μM, respectively. Palmatine and jatrorrhizine showed the weaker inhibitory effect on the formation of the metabolites of berberine. Berberine showed a weak inhibitory effect on the production of coptisine metabolite with an IC50value of 115 μM, and palmatine and jatrorrhizine had little inhibitory effect on the formation of coptisine metabolite. Berberine, coptisine, and jatrorrhizine showed no inhibitory effect on the generation of palmatine metabolite (IC50> 200 μM). The findings suggested that there are different degrees of metabolic interaction between the four components. Coptisine showed the strongest inhibition toward berberine metabolism.

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