Levy R H, Hachad H, Yao C, Ragueneau-Majlessi I
University of Washington, H-272 Health Sciences Center, Box 357610, Seattle, WA 98195, USA.
Curr Drug Metab. 2003 Oct;4(5):371-80. doi: 10.2174/1389200033489325.
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.
