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Cytochrome P450 Inhibition 2014-02-21 손한표 Index Overview Introduction CYP Inhibition Fundamentals Effects of CYP Inhibition CYP Inhibition Case Studies Structure Modification Strategies to Reduce CYP Inhibition Reversible and Irreversible CYP Inhibition Other DDI Issues Methods Problems Overview Drug-drug interactions can occur when two drugs are coadministered and compete for the same enzyme. In cytochrome P450(CYP) inhibition, one drug(“perpetrator”) binds to the isozyme and the other drug(“victim”) is excluded from metabolism, thus increasing to a toxic concentration Irreversible binding inactivates CYP and is termed mechanismbased inhibition CYP inhibition can cause withdrawal from clinical use or restrictive labeling for a drug Introduction Many patients receive more than one drug at a time; physicians must be careful to avoid drug-drug interaction. A major DDI concern is cytochrome P450 (CYP) inhibition. Because of CYP inhibition effects on clearance and halftime, it has become an important concern with the FDA and at pharmaceutical companies. CYP Inhibition Fundamentals Cl = Clearance rate Clint(i) ≈ Clint/[1+(I+Ki)] CYP Inhibition Fundamentals CYP3A4 CYP2D6 CYP Inhibition Fundamentals Effects of CYP Inhibition Terfeneadine Erythromycin Effects of CYP Inhibition In vitro In vivo Coincubation method Cmax & Ki Guidelines Plasma protein binding of inhibitor Effects of CYP Inhibition Effects of CYP Inhibition Effects of CYP Inhibition CYP3A4 vs CYP2C19 Plasma protein binding Cmax & Ki CYP Inhibition Case Studies CYP Inhibition Case Studies CYP Inhibition Case Studies Consequences of Chirality on CYP Inhibition (+)-isomer : CYP2C9 more inhibition! Quinidine : CYP2D6 Inhibition Quinine : NOT inhibtion Structure Modification Strategies to Reduce CYP Inhibition Structure Modification Strategies to Reduce CYP Inhibition Structure Modification Strategies to Reduce CYP Inhibition Structure Modification Strategies to Reduce CYP Inhibition Reversible and Irreversible CYP Inhibition Inhibition Reversible Irreversible mechanism-dependant Formation covalent bond Tight quasiirreversible binding Reversible and Irreversible CYP Inhibition Other DDI Issues DDI Issues Candidate as Victim to a mechanism Inhibition Perpetrator Multiple pathway Candidate as a Victim or Perpetrator at a Transporter Using DDI Candidate as a Victim or Perpetrator of Metabolic Enzyme Induction Induce the metabolizing enzyme Method Fluorescent Assay for CYP Inhibition In Silico Single Substrate HLM Assay for CYP Inhibition Method In Vitro CYP Inhibition assessment strategy Cocktail Substrate HLM Assay for CYP Inhibition Double Cocktail Assay for CYP Inhibition Method In Silico Two software companies offer tools for predicting CYP Inhibition. Name Company Web site KnowItAll Biorad www.biorad.com ADMENSA Inpharmatica www.inpharmatica.com Method In vitro CYP Inhibition Methods Assays can be distinguished by four method elements CYP material – rhCYP, HLM Substrate compounds – Fluorogenic , Drug substrate. Detection method – Fluoroscence, LC/MS/MS, Radioactivity, Luminescence Strategy of analysis Method Method Strategy of analysis 1.Fluorescent Assay for CYP Inhibition Individual rhCYP isoenzymes, individual fluorescent substrate, fluoroescent detection. Method Strategy of analysis 2.Single Substrate HLM Assay for CYP Inhibition HLM, individual specific drug substrates, LC/MS/MS detection Method Strategy of analysis 3.Cocktail Substrate HLM Assay for CYP Inhibition HLM, cocktail of specific drug substrates, LC/MS/MS detection Three problems exist. 1.The native abundance of each of the CYP isozymes varies widely in HLM. 2.Many test compounds are highly metabolized by the HLM. 3.Nonspecific protein binding to the HLM material. Method Strategy of analysis 4.Double Cocktail Assay for CYP Inhibition Cocktail of rhCYP isozymes, cocktail of drug substrates, LC/ MS/MS detection. Double Cocktail name comes from using two kinds of cocktail; cocktail of rhCYP isozymes plus specific drug substrates. Problems 1.For initial CYP inhibition screening, a useful goal is an IC50 greater than what concentration? 10𝜇M 2.For human studies, Ki should be what? At what concentration is there likely to be CYP inhibition? greater than 10times than Cmax. When concentration greater than Ki 3.Why was Saldane removed from the market? because its metabolism at CYP3A4 was inhibited by 3A4 inhibitor. Such as erythromycin. Problems 4.what is difference between reversible and mechanismbased CYP inhibition? How can you distinguish these mechanism? Reversible : inhibitor binds and releases from the enzyme. Irreversible : inhibitor binds to enzyme by covalent interaction or strong complexation interatction. Time dependacy of inhibition. 5. How might you modify the following structure to reduce CYP inhibition? Problems 6.What is the risk associated with CYP inhibition? A. a coadministered drug is metabolized too quickly, B. a compound is not stable, C. a coadministered drug is not metabolized quickly enough, D. an isozyme may be induced. 7. Should CYP inhibition be used to estimate metabolic stability? NO