Cytochrome P450 Turnover: Regulation of Synthesis and Degradation, Methods for Determining Rates, and Implications for the Prediction of Drug Interactions

In vivo enzyme levels are governed by the rates of de novo enzyme synthesis and degradation. A current lack of consensus on values of the in vivo turnover half-lives of human cytochrome P450 (CYP) enzymes places a significant limitation on the accurate prediction of changes in drug concentration-time profiles associated with interactions involving enzyme induction … Continued

A Critical Evaluation of the Experimental Design of Studies of Mechanism-based Enzyme Inhibition, with Implications for In Vitro-In Vivo Extrapolation

The published literature on mechanism based inhibition (MBI) of CYPs was evaluated with respect to experimental design, methodology and data analysis. Significant variation was apparent in the dilution factor, ratio of preincubation to incubation times and probe substrate concentrations used, and there were some anomalies in the estimation of associated kinetic parameters (k(inact), K(I), r). … Continued

Interplay of Metabolism and Transport in Determining Oral Drug Absorption and Gut Wall Metabolism: A Simulation Assessment Using the “Advanced Dissolution, Absorption, Metabolism (ADAM)” Model

Bioavailability of orally administered drugs can be influenced by a number of factors including release from the formulation, dissolution, stability in the gastrointestinal (GI) environment, permeability through the gut wall and first-pass gut wall and hepatic metabolism. Although there are various enzymes in the gut wall which may contribute to gut first pass metabolism, Cytochrome … Continued

Sex Differences in the Clearance of CYP3A4 Substrates: Exploring Possible Reasons for the Substrate Dependency and Lack of Consensus

Sex differences in the clearance of substrates of Cytochrome P4503A (CYP3A4) have been reported frequently although there has been no consensus on reasons for variation in observations amongst drugs which are seemingly all dependent on this enzyme for their metabolism. Moreover, these observations could not be replicated in all studies even when investigating the same … Continued

Physiologically-based Pharmacokinetic (PBPK) Models for Assessing the Kinetics of Xenobiotics During Pregnancy: Achievements and Shortcomings

The physiological changes that occur in the maternal body and the placental-foetal unit during pregnancy influence the absorption, distribution, metabolism, and excretion (ADME) of xenobiotics. These include drugs that are prescribed for therapeutic reasons or chemicals to which women are exposed unintentionally from the surrounding environment. The pregnancy physiologically-based pharmacokinetic (p-PBPK) models developed for theoretical … Continued

Prediction of Drug-drug Interactions Arising from Mechanism-based Inactivation: Key Input Parameters and Impact on Risk Assessment

As the prevalence of polypharmacy increases with our aging population, the propensity for adverse drug-drug interactions arising from the altered metabolism of co-administered medicines remains an important consideration for drug development. Mechanism-based inactivation (MBI) of the cytochrome P450 enzyme system is responsible for many clinically relevant drug-drug interactions (DDIs) due to the irreversible and long-lasting … Continued

Towards a Quantitative Framework for the Prediction of DDIs Arising from Cytochrome P450 Induction

Although CYP induction is not generally considered to be as clinically relevant as CYP inhibition, there are important examples where induction has caused both therapeutic failure, due to insufficient exposure to parent drug, and toxicity, mediated by increased formation of reactive metabolites. Furthermore, while there has been considerable progress in the extrapolation of in vitro … Continued

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 … Continued

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, … Continued

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