Implications of Mechanism-based Inhibition of CYP2D6 for the Pharmacokinetics and Toxicity of MDMA

The aim of this study was to model the in vivo kinetic consequences of mechanism-based inhibition (MBI) of CYP2D6 by 3,4 methylenedioxymethamphetamine (MDMA, ecstasy). A model with physiologically-based components of drug metabolism was developed, taking account of change in the hepatic content of active CYP2D6 due to MBI by MDMA. Based on the in vitro […]

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The Impact of Experimental Design on Assessing Mechanism-based Inactivation of CYP2D6 by MDMA (Ecstasy)

MDMA (3-4-methylenedioxymethamphetamine, commonly known as Ecstasy) is a potent mechanism-based inhibitor (MBI) of cytochrome P450 2D6 (CYP2D6), causing quasi-irreversible inhibition of the enzyme in vitro. An evaluation of the in vivo implications of this phenomenon depends on the accuracy of the estimates of the parameters that define the inhibition in vitro, namely kinact (the maximal […]

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Prediction of Clearance of Eleven Drugs and Associated Variability in Neonates

Prediction of the exposure of neonates, infants and children to xenobiotics is likely to be more successful using physiologically based pharmacokinetic models than simplistic allometric scaling, particularly in younger children. However, such models require comprehensive information on the ontogeny of anatomical, physiological and biochemical variables; data that are not available from single sources. The Simcyp® […]

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Prediction of Metabolic Drug Clearance in Humans: In Vitro-In Vivo Extrapolation vs Allometric Scaling

Previously in vitro-in vivo extrapolation (IVIVE) with the Simcyp Clearance and Interaction Simulator® has been used to predict the clearance of 15 clinically used drugs in humans. The criteria for the selection of the drugs were that they are used as probes for the activity of specific cytochromes P450 (CYPs) or have a single CYP […]

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