Assessment of drug-drug interactions: concepts and approaches.
1. A priori knowledge of the enzyme inhibitory potential of new drug entities and the drug-metabolizing enzymes involved can be used in support of important decisions on the future progress of a drug in clinical development. 2. Important advances in the knowledge of human drug-metabolizing enzymes have largely fuelled the integration of in vitro drug metabolism and clinical drug interaction studies for use in drug development programmes. 3. The likelihood of correctly predicting in vivo drug-drug interactions appears highly dependent on selecting the correct enzyme inhibition model for use in deriving the inhibitor constant (Ki) and correctly determining the available concentration of inhibitor at the active site of the enzyme(s) of interest. 4. The uncertainty and inaccuracy of predicting the extent and duration of in vivo drug interactions currently stems from a lack of definitive models by which to assess likely substrate and inhibitor concentrations at the active site of metabolism. Additional issues contributing to the uncertainty of predicting drug interactions include assumptions of the contribution of presystemic drug extraction and the effect of inhibitors on the processes involved. 5. This review considers the practical aspects of in vitro enzyme inhibition studies and the use of in vitro-in vivo correlation approaches described in the literature to predict in vivo drug-drug interactions.
Weaver
R J
RJ
Division of Metabolism & Pharmacokinetics, Servier Research and Development Ltd, Slough, UK. weaver@netgrs.demon.co.uk
D000818:Animals; D020134:Catalytic Domain; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D015195:Drug Design; D004347:Drug Interactions; D004789:Enzyme Activation; D004790:Enzyme Induction; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D008954:Models, Biological; D004364:Pharmaceutical Preparations / Q000378:metabolism; D011485:Protein Binding
D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D004364:Pharmaceutical Preparations; D003577:Cytochrome P-450 Enzyme System