Introduction to Pharmacokinetics—ADME

Pharmacokinetics

In other lessons, we've touched on a branch of pharmacology, pharmacodynamics. Pharmacodynamics was all about examining the behaviour of the drug and its target in close proximity and the downstream effects immediately after the two interact. You probably noticed something was missing from the perspective of pharmacodynamics: the journey of the drug before and after. Drugs start outside the body, somehow they make their way into the body and to their site of action and ultimately they leave the body.

You may recall pharmacodynamics described as "what the drug does to the body". Pharmacokinetics describes the inverse of this: "what the body does to the drug". Pharmacokinetics describes how drugs enter the body, travel around the body, get transformed by the body and leave the body.

ADME

A popular acronym for remembering the various pharmacokinetic processes is "ADME"…

• Absorption—How drugs enter the body
• Distribution—How drugs move around the body
• Metabolism—How drugs are transformed by the body
• Excretion—How drugs leave the body

These four processes——absorption, distribution, metabolism and excretion—so succinctly describe pharmacokinetics that "ADME" (like "add-mee") is practically synonymous with "pharmacokinetics".

From the outset, it's worth mentioning that the ADME pharmacokinetics model is not linear. Processes such as enterohepatic recirculation allow excreted drugs to be reabsorbed and other processes complicate the simple linear model of A → D → M → E.

Absorption

The first chapter of the drug's story begins with entering the body in the absorption phase. Most drug are given orally (eg as tablets, capsules, liquid) and absorbed through the gastrointestinal tract. This is a surprisingly treacherous route to enter the body. The stomach presents a strongly acidic environment that can degrade many compounds including drugs. The intestines, the site of most drug absorption, is mostly impermeable to large drug-like molecules; the intestines are optimised to take in nutrients from food but leave out toxins (many drugs appear toxic to the body). Finally, after absorption, the blood delivers the drug immediately to the liver where it could be metabolised into an inactive substance and made useless (again, the body has systems to avoid harm by toxins in the food we eat). This shows some of the challenges in drug absorption and explains why only a fraction of an administered dose ever reaches the systemic circulation.

Distribution

After being absorbed, the drug can move around the body to different organs, tissues and cells in the distribution phase. The most important vehicle of drug distribution is the blood. Following absorption of drug from the small intestines, drugs make their way to the heart through the venous system (via the portal system for hydrophilic drugs or the thoracic lymphatic duct for lipophilic drugs). From the heart, drugs can be taken to any organ in the body. The distribution phase also coverse movement from the blood into tissues and cells where most drugs act.

Metabolism

The metabolism phase (separated into phase I metabolism and phase II metabolism) describes the various chemical changes that occur to the drug molecule carried out by enzymes. Most drug metabolism is performed by enzymes which exist (from evolution) to protect us from toxins in the food we eat. Therefore, most of the metabolic changes give products (called "metabolites") that are inactive or can be removed from the body more easily. Less commonly, metabolism can produce metabolites that are more active or sometimes toxic.

Excretion

The excretion phase phase describes the processes of removing drug from the body. Most excretion is carried out by the kidneys which filter drug molecules from the blood and put them into the urine. Less commonly, the liver can place drug molecules into the bile which is excreted as faeces. Minor routes of excretion include sweat, saliva, hair, respiration and breast milk.

Modelling Drug Disposition

Concentration-Time Curves

By measuring the concentration of drug in the patient's plasma at regular timed intervals, we can construct a concentration-time curve that reflects how much drug is in the patient's blood over time.

The figure below shows a typical concentration vs time plot for a drug adminsitered as a tablet by mouth. Some key features to note is the brief lag time reflecting the tablet's journey from the mouth to the intestines, the rapid rise in plasma drug concentration reflecting absorption from the intestines and the slow decline reflecting the gradual metabolism and excretion of the drug from the body.

These concentration-time curves are very important to clinical pharmacokinetics because pharmacologists can extract a lot of useful information from them. Since drug efficacy and toxicity are closely tied to plasma concentrations, concentration-time graphs can tell us when to expect the drug action to begin, how long it will last, how frequently we should give doses etc.

Compartmental Models

Compartment models break up the body into discreet containers (eg inside the blood vessels, extracellular spaces etc) between which, drug can flow at varying rates (imagine a network of buckets connected by hoses). These models are useful because they allow predictions about drug concentrations in any given tissue at any given time (if the pharmacokinetic parameters of the tissue and drug are known).

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