Expert Opinion on Drug Metabolism & Toxicology 

About: Expert Opinion on Drug Metabolism & Toxicology is an academic journal published by Informa. The journal publishes majorly in the area(s): Medicine & Pharmacokinetics. It has an ISSN identifier of 1742-5255. Over the lifetime, 1943 publications have been published receiving 61345 citations. The journal is also known as: Expert opinion on drug metabolism and toxicology.

Species differences between mouse, rat, dog, monkey and human CYP-mediated drug metabolism, inhibition and induction.

Abstract: Animal models are commonly used in the preclinical development of new drugs to predict the metabolic behaviour of new compounds in humans. It is, however, important to realise that humans differ from animals with regards to isoform composition, expression and catalytic activities of drug-metabolising enzymes. In this review the authors describe similarities and differences in this respect among the different species, including man. This may be helpful for drug researchers to choose the most relevant animal species in which the metabolism of a compound can be studied for extrapolating the results to humans. The authors focus on CYPs, which are the main enzymes involved in numerous oxidative reactions and often play a critical role in the metabolism and pharmacokinetics of xenobiotics. In addition, induction and inhibition of CYPs are compared among species. The authors conclude that CYP2E1 shows no large differences between species, and extrapolation between species appears to hold quite well. In contrast, the species-specific isoforms of CYP1A, -2C, -2D and -3A show appreciable interspecies differences in terms of catalytic activity and some caution should be applied when extrapolating metabolism data from animal models to humans.

Non-P450 aldehyde oxidizing enzymes: the aldehyde dehydrogenase superfamily.

Abstract: Background: Aldehydes are highly reactive molecules. While several non-P450 enzyme systems participate in their metabolism, one of the most important is the aldehyde dehydrogenase (ALDH) superfamily, composed of NAD(P)+-dependent enzymes that catalyze aldehyde oxidation. Objective: This article presents a review of what is currently known about each member of the human ALDH superfamily including the pathophysiological significance of these enzymes. Methods: Relevant literature involving all members of the human ALDH family was extensively reviewed, with the primary focus on recent and novel findings. Conclusion: To date, 19 ALDH genes have been identified in the human genome and mutations in these genes and subsequent inborn errors in aldehyde metabolism are the molecular basis of several diseases, including Sjogren-Larsson syndrome, type II hyperprolinemia, γ-hydroxybutyric aciduria and pyridoxine-dependent seizures. ALDH enzymes also play important roles in embryogenesis and development, neurotransmissi...

The Simcyp® population-based ADME simulator

Abstract: The Simcyp population-based absorption, distribution, metabolism and excretion simulator is a platform and database for 'bottom-up' mechanistic modelling and simulation of the processes of oral absorption, tissue distribution, metabolism and excretion of drugs and drug candidates in healthy and disease populations. It combines experimental data generated routinely during preclinical drug discovery and development from in vitro enzyme and cellular systems and relevant physicochemical attributes of compound and dosage form with demographic, physiological and genetic information on different patient populations. The mechanistic approach implemented in the Simcyp Simulator allows simulation of complex absorption, distribution, metabolism and excretion outcomes, particularly those involving multiple drug interactions, parent drug and metabolite profiles and time- and dose-dependent phenomena such as auto-induction and auto-inhibition.This review describes the framework and organisation of the simulator and how it combines the different categories of information.

Caco-2 cell permeability assays to measure drug absorption.

Abstract: Caco-2 cells are a human colon epithelial cancer cell line used as a model of human intestinal absorption of drugs and other compounds. When cultured as a monolayer, Caco-2 cells differentiate to form tight junctions between cells to serve as a model of paracellular movement of compounds across the monolayer. In addition, Caco-2 cells express transporter proteins, efflux proteins, and Phase II conjugation enzymes to model a variety of transcellular pathways as well as metabolic transformation of test substances. In many respects, the Caco-2 cell monolayer mimics the human intestinal epithelium. One of the functional differences between normal cells and Caco-2 cells is the lack of expression of the cytochrome P450 isozymes and in particular, CYP3A4, which is normally expressed at high levels in the intestine. However, Caco-2 cells may be induced to express higher levels of CYP3A4 by treatment with vitamin D3. Caco-2 cell monolayers are usually cultured on semipermeable plastic supports that may be fitted i...

The Caco-2 cell monolayer: usefulness and limitations

Abstract: Background: The Caco-2 monolayer has been used extensively for the high-throughput screening of drug permeability and identification of substrates, inhibitors, and inducers of intestinal transporters, especially P-glycoprotein (P-gp). Traditionally, the Caco-2 monolayer is viewed as a single barrier rather than a polarized cell monolayer consisting of metabolic enzymes that are sandwiched between two membrane barriers with distinctly different transporters. Objective: This review addressed the usefulness and limitations of the Caco-2 cell monolayer in drug discovery and mechanistic studies. Methods: This mini-review covered applications of the Caco-2 monolayer, clarified misconceptions, and critically addressed issues on data interpretation. Conclusion: The catenary model extends the usefulness of Caco-2 monolayer and provides proper mechanistic insight and data interpretation.