By Guofeng You, Marilyn E. Morris, Binghe Wang
Drug-Drug Interactions in Pharmaceutical improvement comprehensively experiences the correct technology, commercial perform, and regulatory organisation positions on drug-drug interactions. It specializes in the overview of capability drug-drug interactions, permitting researchers to deal with chance elements earlier than a drug is placed to marketplace. The publication covers either scientific and nonclinical facets for figuring out drug-drug interactions in addition to in vitro and in vivo stories to be used in learning interactions on the drug discovery level.
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REFERENCES 29 Uttamsingh V, Lu C, Miwa G, Gan LS. Relative contributions of the ﬁve major human cytochromes P450, 1A2, 2C9, 2C19, 2D6, and 3A4, to the hepatic metabolism of the proteasome inhibitor bortezomib. Drug Metab Disp 2005;33:1723–1728. Vazquez E, Whitﬁeld L. Seldane warnings. Posit Aware 1997;8:12. Vickers AE, Sinclair JR, Zollinger M, Heitz F, Glanzel U, Johanson L, Fischer V. Multiple cytochrome P450s involved in the metabolism of terbinaﬁne suggest a limited potential for drug-drug interactions.
This phenomenon has been termed ‘‘differential kinetics’’ and is discussed in more detail by Shou et al. (2001a, 2001b). Although there is substantial evidence for atypical kinetics in vitro and some evidence in vivo, the true clinical relevance of CYP450 enzymatic activation needs further investigation but should be considered in the in vitro–in vivo scaling of kinetic data. 3 USE OF IN VITRO KINETIC DATA TO PREDICT IN VIVO CLEARANCE In vitro–in vivo scaling in the context of this chapter will focus on the prediction of in vivo clearance from in vitro kinetic data generated from hepatocytes or HLMs.
IC50 is generally determined by plotting the log of the relative activity (activity in the presence of the inhibitor as a percent of the activity of the negative control (solvent control)), and then estimate the concentration yielding 50% relative activity using linear regression analysis. , 2001). Ki can be determined using Dixon plot with the reciprocal of the activity as the y-axis, and inhibitor concentration as the x-axis. , 2001). , 2001). Most P450 inhibitors act via reversible (competitive or noncompetitive mechanisms) with which their inhibitory potential can be estimated from their IC50 or Ki values.