Prediction of Intestinal First-pass Drug Metabolism

Despite a lower content of many drug metabolising enzymes in the intestinal epithelium compared to the liver (e.g. intestinal CYP3A abundance in the intestine is 1% that of the liver), intestinal metabolic extraction may be similar to or exceed hepatic extraction. Modelling of events on first-pass through the intestine requires attention to the complex interplay […]

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Disparity in Holoprotein/Apoprotein Ratios of Different Standards Used for Immunoquantification of Hepatic Cytochrome P450 Enzymes

An analysis of reported hepatic abundances of CYP3A4 and 3A5 indicated that values determined by immunoquantification using commercially available, unpurified recombinant enzymes as standards are significantly lower than those determined using purified enzymes or human liver microsomes characterized with lysosomal peptides (CYP3A4: mean 45 versus 121 pmol/mg protein, p < 0.01; CYP3A5: mean 28 versus […]

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Inactivation of CYP2D6 by Methylenedioxymethamphetamine in Different Recombinant Expression Systems

Recombinantly expressed CYP450 systems (rCYPs) are often used to screen for irreversible/quasi-irreversible enzyme inhibitors during drug development. The concentration- and time-dependent inactivation of CYP2D6 by methylenedioxymethamphetamine (MDMA) was compared in three different rCYP2D6 systems (yeast microsomes, Supersomes™ and Bactosomes™) under the conditions of the most commonly used protocols in assessing mechanism-based inactivation (MBI). MDMA (2-20µM) […]

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Theoretical Assessment of a New Experimental Protocol for Determining Kinetic Values Describing Mechanism (time)-based Enzyme Inhibition

We have shown previously that the conventional experimental protocol (CEP) used to characterise mechanism-based enzyme inhibition (MBI) of drug metabolism in vitro may introduce substantial bias in estimates of the relevant kinetic parameters. The aim of this study was to develop and assess, by computer simulation, an alternative, mechanistically-based experimental protocol (MEP). This protocol comprises […]

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The Use of Mechanistic DM-PK-PD Modeling to Assess the Power of Pharmacogenetic Studies—CYP2C9 and Warfarin as an Example

The aim of this study was to assess the power of in vivo studies needed to discern the effect of genotype on pharmacokinetics (PK) and pharmacodynamics (PD) using CYP2C9 and (S)-warfarin as an example. Information on the in vitro metabolism of (S)-warfarin and genetic variation in CYP2C9 was incorporated into a mechanistic population-based PK-PD model. […]

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Simulation and Prediction of In Vivo Drug Metabolism in Human Populations from In Vitro Data

The perceived failure of new drug development has been blamed on deficiencies in in vivo studies of drug efficacy and safety. Prior simulation of the potential exposure of different individuals to a given dose might help to improve the design of such studies. This should also help researchers to focus on the characteristics of individuals […]

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Scaling Factors for the Extrapolation of In Vivo Metabolic Drug Clearance from In Vitro Data: Reaching a Consensus on Values of Human Microsomal Protein and Hepatocellularity per Gram of Liver

Reported predictions of human in vivo hepatic clearance from in vitro data have used a variety of values for the scaling factors human microsomal protein (MPPGL) and hepatocellularity (HPGL) per gram of liver, generally with no consideration of the extent of their inter-individual variability. We have collated and analysed data from a number of sources, […]

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Prediction of Plasma Protein Binding Displacement and Its Implications for Quantitative Assessment of Metabolic Drug-drug Interactions from In Vitro Data

Although displacement from plasma protein binding (dPB) is usually of little clinical significance, it should be taken into account when interpreting changes in total plasma concentrations of drugs subject to metabolically based drug-drug interactions (mDDI). The aim of this study was to develop an approach to predict changes in the free fractions (fu) of pairs […]

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