Drug Metabolism – From In Vitro to In Vivo, From Simple to Complex

Abstract

Drug metabolism is the crucial part of pharmaco-and toxicokinetics and consequently is associated with both desirable and adverse effects of most xenobiotics, compounds foreign to the body. This minireview follows some advances of the field over the last 50 years or so through the experiences and work of one scientist. Thus, this minireview represents a rather personal view of research in one research field. Drug metabolism is affected and controlled by a huge number of factors and conditions such as individual development, species differences, drug-drug interactions and various environmental, host and genetic factors working via a variable set of regulatory mechanisms. All these different factors create wide individual, population and species variability with obvious repercussions to clinical drug therapy and chemical risk assessment. This minireview also provides glimpses to methodological developments over recent decades and ends up presenting a few promising approaches and techniques such as various omics and high-content and high-throughput techniques feeding huge amounts of data to computational integration and modelling, which constitute the basis for systems or network pharmacology and toxicology.

Role of Cytochrome P450 2C8 in Drug Metabolism and Interactions

“…The general aspects as well as the potential pitfalls of in vitro studies and extrapolations are well covered by many excellent review articles and guidelines (Houston and Galetin, 2008;Pelkonen et al, 2008;Grimm et al, 2009;EMA, 2012b;Pelkonen, 2015; http://www.fda.gov/Drugs/ DevelopmentApprovalProcess/DevelopmentResources/ DrugInteractionsLabeling/ucm093664.htm). Therefore, this review focuses on issues that are directly related to CYP2C8, i.e., in vitro methods used for measurement of CYP2C8 activity (e.g., to test the potential of the investigational drug to inhibit CYP2C8 activity) and reaction phenotyping (does CYP2C8 metabolize the drug) and in vivo studies to characterize the drug interaction potential of the new drug (either as a perpetrator or victim drug).…”