The set of properties that characterize the effects of the body on a drug is called:

The main aim of drug development is to get a compound that has a therapeutic effect into the form of a medicine we can dose to patients. A drug must reach the site of action, exert its pharmacological effects, and be eliminated in a reasonable timeframe – preferably to allow once-per-day dosing. Characterization of absorption, distribution, metabolism, and excretion (ADME) properties help to explore and explain how pharmacokinetic processes happen, so as to provide safety considerations of a new drug on which risk-based assessments can be made.

Absorption, distribution, metabolism, and excretion are processes that together describe a drug’s overall disposition via pharmacokinetics, or what the body does to a drug. ADME data can be collected at many stages in a drug’s development pipeline. In discovery and lead optimization, drug developers may make chemical modifications to drug candidates to optimize ADME properties1. As a drug moves forward through preclinical development and clinical phases, in vitro and in vivo studies provide critical information needed to meet regulatory expectations and equip drug developers to make informed decisions.

Absorption is the process by which a drug enters the bloodstream. There are many possible routes of administration, but the two most common are intravenous and oral. If a drug is administered intravenously, the absorption phase is skipped as the drug immediately enters circulation. However, many drugs are dosed orally because it makes it possible for patients to self-administer. When a xenobiotic is ingested, it travels first through the gastrointestinal tract, then to the liver via the portal circulation, and from there enters systemic circulation during which it can be distributed to the site of action.

Small molecules typically traverse membranes throughout this process, sometimes via passive transport, but often by way of proteins known as drug transporters. Drug transport can be a critical component of a drug’s disposition in many steps of the pharmacokinetic journey, and preclinical studies should be conducted to provide information on how a drug interacts with various transporters – as either substrates or inhibitors.

A drug’s absorption may be impacted by many factors, including molecular weight, topological polar surface area (TPSA), solubility, ionization, and other physicochemical properties. Importantly, absorption data can be helpful in determining the potential for how much of the drug reaches the bloodstream after oral administration. The first-pass effect (among other factors) after oral absorption will ultimately determine bioavailability.

Distribution

Metabolism

Metabolism is the conversion of generally more lipophilic xenobiotic compounds to hydrophilic metabolites that can be eliminated from the body via excretion2. Metabolism of a drug involves enzymes and several investigative studies may be needed to identify major metabolites and relevant metabolic pathways.

Excretion

Excretion is the irreversible loss of a substance from the system. In most cases, all drug-related material, including parent drug and metabolites are eventually cleared from the body. It is important to characterize which routes of excretion are most important. Excretion commonly occurs by function of the kidney (urine) or liver (bile/feces), but the drug can also be excreted through sweat, tears, or breath.

In vivo excretion studies can help to both identify route(s) of excretion of a compound and characterize drug-related material clearance while monitoring the exposure of drug and metabolites in plasma and other compartments. Animal mass balance studies  use radiolabeled compound to characterize a drug’s excretion path and rate. From this study, quantitative analysis of urine, feces, (in some cases) expired air, and carcass provide a complete picture of how a compound is eliminated from the body and at what rate. Other supportive studies can provide data to further explore biliary excretion (bile duct cannulation method), lymphatic partitioning rate, excretion via milk, and more.

Big Picture: ADME helps drug developers to distinguish ‘good’ drug candidates

Potential drugs need appropriate pharmacokinetic properties to become safe, useable, effective therapeutics. In order to have a ‘good’ pharmacokinetic profile, a drug must:

• Get into the bloodstream (A)
• Move to the site of action (D)
• Remain unchanged long enough to have a therapeutic effect and then be converted to safe metabolites (M)
• Be adequately cleared (E)

We offer test systems and contract services to clients who need high-quality, dependable in vitro and in vivo ADME data. In addition to utility in understanding pharmacokinetics of your drug and meeting regulatory requirements for IND submission, ADME data can be used to support or precede studies investigating drug-drug interaction (DDI) potential of a compound.

By ensuring your drug is supported by well-designed, carefully executed preclinical studies, you can maximize your drug’s chance of success in the clinic. Our team has been building experience for 25 years; our experts have just about seen it all. When it comes to your compound’s in vitro and in vivo ADME data, we can offer you quality, reliability, and a consultative approach.

1. Loftsson, T. “Physicochemical Properties and Pharmacokinetics.­” Essential Pharmacokinetics, 2015. Pages 85-104. doi: 10.1016/b978-0-12-801411-0.00003-2
2. Parkinson et al. “Biotransformation of Xenobiotics”Casarett & Doull’s Toxicology, The Basic Science of Poisons Ninth Edition. McGraw-Hill Education 2018. Page 194.

Next Up: Concepts Related to a Compound’s ADME

Drug-Drug Interaction (DDI) Studies

In vitro preclinical testing methods to predict your drug’s risk of causing a metabolism- or transporter-mediated drug interaction in clinical phases.

Drug Metabolism & Pharmacokientics (DMPK) Testing

Biotransformation pathways and metabolite formation provide critical information to the safety profile of an investigational new compound. DMPK is a discipline in which sponsors can understand how a drug’s metabolism and pharmacokinetics impact safety considerations and overall disposition.

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Hear more about it

Learn more about how ADME fits in with DMPK and DDI in our ADME 101 overview webinar presented by VP of Scientific Operations, Dr. Joanna Barbara.

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