Drug Metabolism and Pharmacokinetics

Each drug is unique and inadequate ADME properties (i.e., absorption, distribution, metabolism and excretion), can be devastating to otherwise good drug activity; therefore, the selection of the most appropriate DMPK ADME studies including in vitro assays and animal models to be evaluated is vital. Considering all aspects of how compounds of interest get into the body, how they move within the body, and how they get out of the body can help assess the safety and efficacy of a new therapy.

Charles River’s global network of ADME scientists and facilities are positioned to help you design the optimal ADME program to support your drug discovery and development needs. Even though ADME is generally used within the pharmaceutical drug development process, the concept is applicable to nonpharmaceutical moieties such as chemicals, agrochemicals and biocides. As a full service ADME CRO, Charles River can assist across multiple industries.

ADME steps through drug development continuum

In vitro and in vivo DMPK ADME studies enable researchers to make go/no-go decisions on whether a compound should be selected as a drug candidate in the early medicinal chemistry and lead optimization phase of drug discovery. During development, drug metabolism and pharmacokinetic (DMPK) properties will help validate the toxicology studies, support safety evaluations prior to first dose in man, provide human dosimetry data for the clinic and indicate the likelihood of drug-drug interactions.


ADME in Parallel with Efficacy is a Win-Win

ADME in Parallel with Efficacy is a Win-Win

Improved in vitro assays now provide more efficient and effective ADME testing.

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  • Absorption:

    Movement of a drug from its site of administration into the bloodstream is defined as absorption. While most drugs are absorbed by passive permeation, some need carrier-mediated transport. Every drug is different, and many characteristics play a role in the absorption of a drug, like physicochemistry characteristics (e.g., molecular weight, hydrophobicity, solubility), physiological characteristics (e.g., blood flow, intestinal motility, membrane permeability) and biochemical characteristics (e.g., efflux, metabolism) characteristics and the formulation itself.

    ADME studies to consider: aqueous solubility, in vitro permeability, in vitro drug transporters, in vitro dermal absorption and in vivo pharmacokinetics and in vivo dermal absorption.

  • Distribution:

    Once the drug has been absorbed into the bloodstream it is transported or differentially distributed from the blood to the site of action within the body. Not all compounds distribute equally throughout the body. This is determined by the compounds physicochemistry and ability to permeate into tissues and cells and by the blood flow to tissues but also by binding of the compound to proteins and by specific transporter processes.

    ADME studies to consider: in vitro plasma protein binding, in vitro RBC partitioning, melanin binding, in-vitro uptake/efflux transporters, barrier tissue models, in vivo tissue distribution, quantitative whole body autoradiography (QWBA), cerebrospinal fluid collection, in vivo pharmacokinetics.

  • Metabolism:

    In order to facilitate the excretion of a drug from the body, the drug is chemically altered by enzymes to increase its polarity and water solubility. This process is called metabolism. Most metabolism takes place in the liver. The family of enzymes that is mainly involved in the first steps of the metabolic process are the cytochrome P450 enzymes (CYP450). Another important enzyme family that is responsible for a conjugation reaction (glucuronidation) is the UGT family.

    ADME studies to consider: metabolic stability, metabolite profiling/comparative species metabolism, CYP/ UGT characterization, CYP/UGT inhibition, CYP induction, drug-drug interaction studies (DDI), reactive metabolite assessment, covalent binding.

  • Excretion:

    Drug (unchanged) and/or its metabolites can leave the body via different routes of excretion, e.g. urine, bile, feces, expired air, sweat. This can either be a passive process (e.g. glomerular filtration in the kidneys) or an active secretion process mediated by transporters.

    ADME studies to consider: in vitro transporters, mass balance studies (excreta and expired air collection via metabolism cages), bile cannulation models.

At Charles River we have over 400 ADME scientists dedicated to both discovery and development, allowing early compound design and lead candidate selection to flow seamlessly into the development phase. Our discovery and research specialists offer customized screening programs to ensure early and late lead candidate optimization. Development studies are designed to satisfy the requirements of international regulatory authorities and to provide safety data to assess the validity of laboratory species as appropriate toxicological models for humans. Our drug metabolism facilities are networked and utilize validated data management systems for data capture, storage and evaluation.

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Frequently Asked Questions (FAQs) for DMPK ADME Studies