Relationship between extent of inhibition and inhibitor dose: literature evaluation based on the metabolism and transport drug interaction database.
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.
Levy
R H
RH
University of Washington, H-272 Health Sciences Center, Box 357610, Seattle, WA 98195, USA. rhlevy@u.washington.edu
Hachad
H
H
Yao
C
C
Ragueneau-Majlessi
I
I
D000818:Animals; D000963:Antimetabolites / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects*; D016208:Databases, Factual; D003864:Depression, Chemical; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006801:Humans; D004364:Pharmaceutical Preparations / Q000378:metabolism*
D000963:Antimetabolites; D004364:Pharmaceutical Preparations