scholarly journals The Effect of Vinpocetine on Human Cytochrome P450 Isoenzymes by Using a Cocktail Method

2016 ◽  
Vol 2016 ◽  
pp. 1-5 ◽  
Author(s):  
Lingti Kong ◽  
Chunli Song ◽  
Linhu Ye ◽  
Daohua Guo ◽  
Meiling Yu ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Ischemic Stroke ◽  
Drug Metabolism ◽  
Human Liver ◽  
Dose Adjustment ◽  
Biological Activities ◽  
Liver Microsomes ◽  
Inhibitory Effect ◽  
Inhibitory Effects ◽  
Human Cytochrome

Vinpocetine is a derivative of the alkaloid vincamine, which had been prescribed for chronic cerebral vascular ischemia and acute ischemic stroke or used as a dietary supplement for its several different mechanisms of biological activities. However, information on the cytochrome P450 (CYP) enzyme-mediated drug metabolism has not been previously studied. The present study was performed to investigate the effects of vinpocetine on CYPs activity, and cocktail method was used, respectively. To evaluate the effects of vinpocetine on the activity of human CYP3A4, CYP2C9, CYP2C19, CYP2D6, and CYP2E1, human liver microsomes were utilized to incubate with the mixed CYPs probe substrates and the target components. The results indicate that vinpocetine exhibited weak inhibitory effect on the CYP2C9, where the IC50value is 68.96 μM, whereas the IC50values for CYP3A4, CYP2C19, CYP2D6, and CYP2E1 were all over range of 100 μM, which showed that vinpocetine had no apparent inhibitory effects on these CYPs. In conclusion, the results indicated that drugs metabolized by CYP2C9 coadministrated with vinpocetine may require attention or dose adjustment.

scholarly journals Chloramphenicol Is a Potent Inhibitor of Cytochrome P450 Isoforms CYP2C19 and CYP3A4 in Human Liver Microsomes

2003 ◽  
Vol 47 (11) ◽  
pp. 3464-3469 ◽  
Author(s):  
Ji-Young Park ◽  
Kyoung-Ah Kim ◽  
Su-Lyun Kim
Keyword(s):  
Cytochrome P450 ◽  
Drug Interaction ◽  
Human Liver ◽  
Liver Microsomes ◽  
Inhibitory Effect ◽  
Human Liver Microsomes ◽  
Human Cytochrome ◽  
Cytochrome P450 Isoforms ◽  
Potent Inhibitory Effect ◽  
Cyp Isoforms

ABSTRACT The inhibitory effect of chloramphenicol on human cytochrome P450 (CYP) isoforms was evaluated with human liver microsomes and cDNA-expressed CYPs. Chloramphenicol had a potent inhibitory effect on CYP2C19-catalyzed S-mephytoin 4′-hydroxylation and CYP3A4-catalyzed midazolam 1-hydroxylation, with apparent 50% inhibitory concentrations (inhibitory constant [Ki ] values are shown in parentheses) of 32.0 (7.7) and 48.1 (10.6) μM, respectively. Chloramphenicol also weakly inhibited CYP2D6, with an apparent 50% inhibitory concentration (Ki ) of 375.9 (75.8) μM. The mechanism of the drug interaction reported between chloramphenicol and phenytoin, which results in the elevation of plasma phenytoin concentrations, is clinically assumed to result from the inhibition of CYP2C9 by chloramphenicol. However, using human liver microsomes and cDNA-expressed CYPs, we showed this interaction arises from the inhibition of CYP2C19- not CYP2C9-catalyzed phenytoin metabolism. In conclusion, inhibition of CYP2C19 and CYP3A4 is the probable mechanism by which chloramphenicol decreases the clearance of coadministered drugs, which manifests as a drug interaction with chloramphenicol.

scholarly journals Selective Inhibition of Bakuchicin Isolated fromPsoralea corylifoliaon CYP1A in Human Liver Microsomes

2016 ◽  
Vol 2016 ◽  
pp. 1-7 ◽  
Author(s):  
Sun Joo Kim ◽  
Heung Chan Oh ◽  
Youn-Chul Kim ◽  
Gil-Saeng Jeong ◽  
Sangkyu Lee
Keyword(s):  
Human Liver ◽  
Competitive Inhibition ◽  
Biological Activities ◽  
Biological Effects ◽  
Liver Microsomes ◽  
Selective Inhibition ◽  
Human Liver Microsomes ◽  
Inhibition Mechanism ◽  
Inhibitory Effects ◽  
Cyp Isoforms

Bakuchicin is a furanocoumarin isolated fromPsoralea corylifoliaand shows several biological activities. Although there have been studies on the biological effects of bakuchicin, its modulation potency of CYP activities has not been previously investigated. Here, we investigated the inhibitory effects of bakuchicin on the activities of CYP isoforms by using a cocktail of probe substrates in pooled human liver microsomes (HLMs) and human recombinantcDNA-expressedCYP. Bakuchicin strongly inhibited CYP1A-mediated phenacetinO-deethylation with an IC50value of 0.43 μM in HLMs. It was confirmed by human recombinantcDNA-expressedCYP1A1 and CYP1A2 with aKivalue of 0.11 μM and 0.32 μM, respectively. A Lineweaver-Burk plot indicated that the inhibition mechanism of bakuchicin was competitive inhibition. Overall, this is the first study to investigate the potential CYP1A1 and CYP1A2 inhibition associated with bakuchicin and to report its competitive inhibitory effects on HLMs.

scholarly journals The Potential for CYP2D6 Inhibition Screening Using a Novel Scintillation Proximity Assay-Based Approach

2001 ◽  
Vol 6 (4) ◽  
pp. 225-231 ◽  
Author(s):  
Enock Delaporte ◽  
Donald E. Slaughter ◽  
Marjorie A. Egan ◽  
Gregory J. Gatto ◽  
Albie Santos ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
High Throughput ◽  
Human Liver ◽  
High Performance ◽  
Liver Microsomes ◽  
Inhibitory Effect ◽  
Human Liver Microsomes ◽  
Kinetics Parameters ◽  
Scintillation Proximity Assay ◽  
Demethylase Activity

High throughput inhibition screens for human cytochrome P450s (CYPs) are being used in preclinical drug metabolism to support drug discovery programs. The versatility of scintillation proximity assay (SPA) technology has enabled the development of a homogeneous high throughput assay for cytochrome P450 2D6 (CYP2D6) inhibition screen using [O-methyl-'4C]dextromethorphan as substrate. The basis of the assay was the trapping of the 0- demethylation product, [14C]HCHO, on SPA beads. Enzyme kinetics parameters Vm,,. and apparent Ki,, determined using pooled human liver microsomes and microsomes from baculovirus cells coexpressing human CYP2D6 and NADPH-cytochrome P450 reductase, were 245 pmol [14C]HCHO/min/mg protein and 11,tM, and 27 pmol ['4C]HCHO/min/pmol and 1.6,uM, respectively. In incubations containing either pooled microsomes or recombinant CYP2D6, [14C]dextromethorphan 0-demethylase activity was inhibited in the presence of quinidine (IC50 = 1.0,uM and 20 nM, respectively). By comparison, inhibitors selective for other CYP isoforms were relatively weak (IC50 > 25 tM). In agreement, a selective CYP2D6 inhibitory monoclonal antibody caused greater than 90% inhibition of [14C]dextromethorphan O-demethylase activity in human liver microsomes, whereas CYP2C9/19- and CYP3A4/5-selective antibodies elicited a minimal inhibitory effect. SPA-based [14C]dextromethorphan 0-demethylase activity was also shown to correlate (r2 = 0.6) with dextromethorphan O-demethylase measured by high-performance liquid chromatography in a bank of human liver microsomes (N = 15 different organ donors). In a series of known CYP2D6 inhibitors/substrates, the SPA-based assay resolved potent inhibitors (IC50 <2 μM) from weak inhibitors (IC50 ≥ 20 μM). It is concluded that the SPA-based assay described herein is suitable for CYP2D6 inhibition screening using either native human liver microsomes or cDNA-expressed CYP2D6.

STEREOSELECTIVE METABOLISM OF ENDOSULFAN BY HUMAN LIVER MICROSOMES AND HUMAN CYTOCHROME P450 ISOFORMS

2006 ◽  
Vol 34 (7) ◽  
pp. 1090-1095 ◽  
Author(s):  
Hwa-Kyung Lee ◽  
Joon-Kwan Moon ◽  
Chul-Hee Chang ◽  
Hoon Choi ◽  
Hee-Won Park ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Human Liver ◽  
Liver Microsomes ◽  
Human Liver Microsomes ◽  
Stereoselective Metabolism ◽  
Human Cytochrome ◽  
Cytochrome P450 Isoforms

In Vitro Metabolism of a New Neuroprotective Agent, KR-31543 in the Human Liver Microsomes: Identification of Human Cytochrome P450

2004 ◽  
Vol 27 (2) ◽  
pp. 239-245 ◽  
Author(s):  
Hye Young Ji ◽  
Seung-Seok Lee ◽  
Sung-Eun Yoo ◽  
Hosoon Kim ◽  
Dong Ha Lee ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Human Liver ◽  
Liver Microsomes ◽  
Human Liver Microsomes ◽  
In Vitro Metabolism ◽  
Neuroprotective Agent ◽  
Human Cytochrome

Inhibitory Effects of Trospium Chloride on Cytochrome P450 Enzymes in Human Liver Microsomes

1999 ◽  
Vol 85 ◽  
pp. 299-304 ◽  
Author(s):  
Svane Beckmann-Knopp ◽  
Stephan Rietbrock ◽  
Roland Weyhenmeyer ◽  
Ronald H. Böcker ◽  
K. Tobias Beckurts ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Human Liver ◽  
Liver Microsomes ◽  
Human Liver Microsomes ◽  
Cytochrome P450 Enzymes ◽  
Inhibitory Effects ◽  
Trospium Chloride
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