Drug Metabolism in Preclinical Drug Development: A Survey of the Discovery Process, Toxicology, and Computational Tools

Abstract

Increased R & D spending and high failure rates exist in drug development, due in part to inadequate prediction of drug metabolism and its consequences in the human body. Hence, there is a need for computational methods to supplement and complement current biological assessment strategies. In this review, we provide an overview of drug metabolism in pharmacology, and discuss the current in vitro and in vivo strategies for assessing drug metabolism in preclinical drug development. We highlight computational tools available to the scientific community for the in silico prediction of drug metabolism, and examine how these tools have been implemented to produce drug-target signatures relevant to metabolic routes. Computational workflows that assess drug metabolism and its toxicological and pharmacokinetic effects, such as by applying the adverse outcome pathway framework for risk assessment, may improve the efficiency and speed of preclinical drug development.

Art of Making Artificial Liver: Depicting Human Liver Biology and Diseases in Mice

“…The hepatocyte serves as the principal site of drug metabolism (DM) due to the predominant expression of xenobioticsmetabolizing enzymes. 246 In general, DM involves three distinct steps: phase I: modification, phase II: conjugation, and phase III: secretion. In phase I, xenobiotics undergo oxidative modifications mainly facilitated by multiple CYP enzymes.…”

De la investigación a la práctica: fases clínicas para el desarrollo de fármacos

“…Este proceso, por lo regular puede tener una duración 10 años o más, y se ha estimado que se requiere una inversión superior a 1.5 mil millones de dólares por fármaco, sin embargo, en el camino, la mayor parte de dichas moléculas (≈ 90 %) no lograrán llegar a la etapa fi nal del proceso. 2 En general, las pautas actuales en el desarrollo de fármacos (es decir, los diferentes estudios de investigación que se realizan) tienen como prioridad la seguridad de su uso, seguida de su efi cacia. Para este fi n, desde hace años existe un "modelo" para que un fármaco sea aprobado para ser usado en humanos.…”

Protein misfolding diseases: Prospects of pharmacological treatment

“…The last stage of the drug discovery process is the derivatization of ligands. Lead optimization improves some of the properties of molecules, such as lipophilicity, synthetic accessibility, absorption, distribution, metabolism, toxicity and excretion . It should be noted that many hit compounds do not make it to the clinical stage of development as they are, in fact, artefacts, that is, their activity does not depend on a specific, drug‐like interaction with the target protein.…”