In vitro evaluation of reversible and irreversible cytochrome P450 inhibition: current status on methodologies and their utility for predicting drug-drug interactions.
It is widely accepted that today's practice of polypharmacy inevitably increases the incidence of drug-drug interactions (DDIs). Serious DDI is a major liability for any new chemical entity (NCE) entering the pharmaceutical market. As such, pharmaceutical companies employ various strategies to avoid problematic compounds for clinical development. A key cause for DDIs is the inhibition of cytochrome P450 enzymes (CYPs) that are responsible for metabolic clearance of many drugs. Screening for inhibition potency of CYPs by NCEs has therefore become a routine practice during the drug discovery stage. However, in order to make proper use of DDI data, an understanding of the strengths and weaknesses of the various experimental systems in current use is required. An illustrated review of experimental practices is presented with discussion of likely future developments. The combination of high quality in vitro data generation and the application of in vivo CYP inhibition modelling approaches should allow more informed decisions to be made in the search for drug molecules with acceptable DDI characteristics.
Fowler
Stephen
S
Drug Metabolism and Pharmacokinetics, F. Hoffmann La-Roche Ltd., 4070, Basel, Switzerland. Stephen.fowler@roche.com
Zhang
Hongjian
H
D065607:Cytochrome P-450 Enzyme Inhibitors; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D004347:Drug Interactions; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D013379:Substrate Specificity
D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors