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

[ Vol. 4 , Issue. 5 ]

Author(s):

R. H. Levy, H. Hachad, C. Yao and I. Ragueneau-Majlessi   Pages 371 - 380 ( 10 )

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,

Affiliation:

Department of Pharmaceutics, University of Washington, H-272 Health Sciences Center, Box 357610,Seattle, WA 98195, USA.



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