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.

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

Identification of human cytochrome P450 isoforms involved in the 7-hydroxylation of chlorpromazine by human liver microsomes

Life Sciences ◽  
2000 ◽  
Vol 67 (2) ◽  
pp. 175-184 ◽  
Author(s):  
Kazuyoshi Yoshii ◽  
Kaoru Kobayashi ◽  
Mihoko Tsumuji ◽  
Masayoshi Tani ◽  
Noriaki Shimada ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Human Liver ◽  
Liver Microsomes ◽  
Human Liver Microsomes ◽  
Human Cytochrome ◽  
Cytochrome P450 Isoforms

In vitro metabolism of alachlor by human liver microsomes and human cytochrome P450 isoforms

1999 ◽  
Vol 122 (1) ◽  
pp. 27-39 ◽  
Author(s):  
Scott Coleman ◽  
Siming Liu ◽  
Russell Linderman ◽  
Ernest Hodgson ◽  
Randy L Rose
Keyword(s):  
Cytochrome P450 ◽  
Human Liver ◽  
Liver Microsomes ◽  
Human Liver Microsomes ◽  
In Vitro Metabolism ◽  
Human Cytochrome ◽  
Cytochrome P450 Isoforms

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.

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