In Silico Simulations to Assess the In Vivo Consequences of In Vitro Metabolic Drug-drug Interactions

Recently, metabolic drug-drug interactions (M-DDI) have raised some high-profile problems in drug development resulting in restricted use, withdrawal or non-approval by regulatory agencies. The use of in vitro technologies to evaluate the potential for M-DDI has become routine in the drug development process. Nevertheless, in the absence of an integrated approach, their interpretation and value remains the subject of debate, […]

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Assessment of In Vivo CYP2D6 Activity: Differential Sensitivity of Commonly Used Probes to Urine pH

Drug/metabolite ratios (MRs) are used as in vivo markers of enzyme activity. The ratios are potentially confounded by the renal clearance of the drug (urine-based MRs) or metabolite (plasma-based MRs). The authors have investigated the relative sensitivity of urinary MR of 3 in vivo probe substrates of CYP2D6 debrisoquine (DB), dextromethorphan (DM), and metoprolol (MP) […]

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Predicting the Clearance of CYP2C9 Substrates

Recently, Andersson et al. (2004) reported that quantitative predictions of hepatic clearance from in vitro CLint values using the “well- stirred liver” model were not useful. Over-prediction of in vivo clearances of four CYP2C9 substrates was found when plasma binding and nonspecific microsomal binding were ignored, and under- prediction when both were accounted for. We […]

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Prediction of Clearance from Recombinantly Expressed CYPs: Intersystem Extrapolation Factor (ISEF)

Recombinantly expressed human cytochromes P450 (rhCYPs) have been underused for the prediction of human drug clearance (CL). Differences in intrinsic activity (per unit CYP) between rhCYP and human liver enzymes complicate the issue and these discrepancies have not been investigated systematically. We define intersystem extrapolation factors (ISEFs) that allow the use of rhCYP data for […]

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The Effects of Dose Staggering on Metabolic Drug-drug Interactions

The purpose of this study was to investigate the effect of dose staggering on metabolic drug-drug interactions (MDDI). Using Matlab®, anatomical, physiological and biochemical data relating to human pharmacokinetics were integrated to create a representative virtual healthy subject relevant to in vivo studies. The effects of dose staggering on AUC and Cmax were investigated under […]

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In Vivo Indices of Enzyme Activity—The Effect of Renal Impairment on the Assessment of CYP2D6 Activity

Urinary drug metabolite ratios and urinary recoveries of metabolites, have been used to assess specific enzyme activity non-invasively in vivo. These indices are potentially confounded by the effect of renal function. A recent study of the effects of renal impairment has found discrepancies between different indices used to mark CYP2D6 activity based on sparteine and […]

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The Determination of Drug Metabolizing Enzyme Activity In Vivo: Pharmacokinetics and Statistical Issues

Probe substrates for various isoforms of cytochrome P450 and other drug-metabolizing enzymes are now widely used to assess genetic, environmental and ethnic differences in the in vivo metabolism of drugs and other xenobiotics .The key issues in assessing drug-metabolizing enzyme activity in vivo include separation (with the aid of genotyping) of risk and exposure; choice […]

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