DMPK/Tox

Drug Metabolism and Pharmacokinetics (DMPK) is part of a larger group of commonly implemented pharmacological studies referred to as ADME (absorption, distribution, metabolism and elimination).^[1] Determining the DMPK properties of a drug candidate is a part of pharmaceutical company’s screening process and also provides important safety and efficacy data required for regulatory approval. The test index of DMPK mainly includes drug metabolism/biotransformation, pharmacokinetics and pharmacodynamics, toxicokinetics/ toxicodynamics, drug-drug interaction, mechanism of drug absorption and disposition (including transporters), drug delivery and system, analytical method, factors affecting drug metabolism, expression of genes for drug-metabolizing enzymes and pharmacogenetics.^[2] Drug metabolism is the process by which the body breaks down and converts medication, usually through specialized enzymatic systems. This process inactivates many drugs, but some drugs are transformed into metabolites that are also biologically active and others are administered as pro-drugs that must undergo drug metabolism to become biologically active. The primary site of drug metabolism is the liver, which contains a family of isoenzymes known as cytochrome P-450 (labeled CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) with a catabolic activity on certain substrates. Pharmacokinetics (PK) describes how the body affects a specific drug after administration, referring to the movement of the drug into, through and out of the body—the time course of its absorption, bioavailability, distribution, metabolism and excretion. The commonly measured pharmacokinetic parameters include dose, dosing interval, Cmax, tmax, Cmin, volume of distribution, concentration and elimination half-life.^[3] Toxicokinetics (TK) is an application of pharmacokinetics to the study of toxicity, which is used primarily for establishing relationships between exposures in toxicology experiments in animals and the corresponding exposures in humans. For example, controlled acute and repeated toxicokinetic animal studies are used to identify a chemical’s biological persistence, tissue and whole body half-life and its potential to accumulate.
DMPK studies are performed using many of the major tools and technologies available to manage drug discovery and development programs. Major in vitro tools, technologies and services used in DMPK studies are applied to measure the physicochemical properties (including solubility, plasma stability, plasma protein binding, tissue homogenate and liver microsome binding, and RBC partition), drug metabolism, permeability, and Drug-Drug interaction (including CYP inhibition assay, time dependent inhibition, and GSH trapping assay for reactive metabolites). For example, the liver microsome fraction and the whole hepatocyte containing major metabolism enzymes such as CYP450 for phase I metabolism and UGT (UDP-glucuronosyltransferase) for phase II metabolism, are analyzed by in vitro drug metabolism models. Transfected cell line models such as Caco-2 are used in intestinal permeability assays. Moreover, the major in vivo technologies and services (such as GLP-compliant or non-GLP studies, pharmacokinetic studies in standard biological models, oral and percutaneous bioavailability studies) are used to yield in vivo pharmacokinetic data like drug clearance, bioavailability, half life and distribution volume. In addition, the major highly sensitive and selective analytical platforms used in DMPK studies may include HPLC with UV or fluorescence detection and LC-MS.
Toxicology (TOX) is the study of the adverse effects of xenobiotics on the health of humans and animals. Toxicology studies include genotoxicity, cardiac toxicity, hepatotoxicity, mitochondrial toxicity, cytotoxicity and some in vivo toxicology studies. Avoiding drug-induced cardiac arrhythmia is recognized as a major hurdle in the successful development of new drugs. Cardiac toxicity studies investigate parameters such as acquired long QT syndrome caused by drugs that block human ether-a-go-go-related-gene (hERG) K⁺ channels, which delays cardiac repolarization and increases the risk of torsades de pointes arrhythmia (TdP).^[3] hERG channel patch-clamp testing currently is considered a critical component of drug safety evaluation. Importantly, hepatotoxicity is a common and primary cause of drug candidate failure in development. The main content of hepatotoxicity studies include detecting cell viability of primary hepatocytes, as well as monitoring steatosis or phospholipidosis.

Reference Learn More