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Antimicrobial Agents and Chemotherapy, November 2003, p. 3464-3469, Vol. 47, No. 11
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.11.3464-3469.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

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

Ji-Young Park,* Kyoung-Ah Kim, and Su-Lyun Kim

Department of Pharmacology, Gachon Medical School, Incheon, Korea

Received 2 June 2003/ Returned for modification 3 July 2003/ Accepted 12 August 2003

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.

* Corresponding author. Mailing address: Department of Pharmacology, Gachon Medical School, 1198 Kuwol-dong, Namdong-gu, Incheon 405-760 Korea. Phone: 82-32-460-2151. Fax: 82-32-422-5105. E-mail: jypark{at}gachon.ac.kr.

Antimicrobial Agents and Chemotherapy, November 2003, p. 3464-3469, Vol. 47, No. 11
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.11.3464-3469.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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