Relationship Between Extent of Inhibition and Inhibitor Dose: Literature Evaluation Based on the Metabolism and Transport Drug Interaction Database

Author(s): R. H. Levy, H. Hachad, C. Yao, I. Ragueneau-Majlessi

Journal Name: Current Drug Metabolism

Volume 4 , Issue 5 , 2003

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Abstract:

A comprehensive search of the literature was undertaken using the Metabolism and Transport Drug Interaction Database (http: / / depts.washington.edu / didbase / ) to evaluate the relationship between extent of inhibition and inhibitor dose. The search included reversible and irreversible inhibitors in studies conducted in the period 1966-2003. Only twelve inhibitors met the criterion of the search: study population exposed to more than one dose of inhibitor within a given study design. Six were reversible inhibitors: ciprofloxacin, enoxacin, felbamate, fluconazole, fluvoxamine and ketoconazole. The other six (cimetidine, diltiazem, disulfiram, paroxetine, verapamil and ritonavir) are considered irreversible inhibitors. Most of the AUC / Clearance data available for both types of inhibitors suggested evidence of dose-dependent inhibition. In the case of reversible inhibitors, the evidence of dose-dependent inhibition is consistent with a number of recent studies suggesting the determination of in vivo inhibition constants based on plasma concentration of inhibitor.

Keywords: Cytochrome P450,, drug interaction,, dose-dependent inhibition,, mechanism-based inhibition,

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Article Details

VOLUME: 4
ISSUE: 5
Year: 2003
Page: [371 - 380]
Pages: 10
DOI: 10.2174/1389200033489325
Price: $65

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