Chloramphenicol is a potent inhibitor of cytochrome P450 isoforms CYP2C19 and CYP3A4 in human liver microsomes

Antimicrob Agents Chemother. 2003 Nov;47(11):3464-9. doi: 10.1128/aac.47.11.3464-3469.2003.

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 [K(i)] values are shown in parentheses) of 32.0 (7.7) and 48.1 (10.6) microM, respectively. Chloramphenicol also weakly inhibited CYP2D6, with an apparent 50% inhibitory concentration (K(i)) of 375.9 (75.8) microM. 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.

MeSH terms

  • Anti-Bacterial Agents / pharmacology*
  • Anticonvulsants / metabolism
  • Aryl Hydrocarbon Hydroxylases / antagonists & inhibitors*
  • Chloramphenicol / pharmacology*
  • Chromatography, High Pressure Liquid
  • Cytochrome P-450 CYP2C19
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme Inhibitors*
  • DNA, Complementary / biosynthesis
  • DNA, Complementary / genetics
  • Drug Interactions
  • Enzyme Inhibitors*
  • Humans
  • In Vitro Techniques
  • Kinetics
  • Microsomes, Liver / drug effects
  • Microsomes, Liver / enzymology*
  • Mixed Function Oxygenases / antagonists & inhibitors*
  • Phenytoin / metabolism

Substances

  • Anti-Bacterial Agents
  • Anticonvulsants
  • Cytochrome P-450 Enzyme Inhibitors
  • DNA, Complementary
  • Enzyme Inhibitors
  • Phenytoin
  • Chloramphenicol
  • Mixed Function Oxygenases
  • Aryl Hydrocarbon Hydroxylases
  • CYP2C19 protein, human
  • CYP3A protein, human
  • Cytochrome P-450 CYP2C19
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human