What is pharmacokinetics?

Pharmacokinetics is the science of what happens to drugs in the body (drug disposition). It uses mathematics to quantify the drug’s journey from absorption to distribution, metabolismand elimination and describes how these processes change over time and in relation to one another. This can get complicated – even incomprehensible to the average health professional – but a broad understanding of the main concepts are what is really needed in daily clinical practice. This is a general summary of these concepts; more detail is readily available online.

 

Physiological steps in drug disposition

Absorption: Absorption is the process by which a drug reaches the systemic circulation. There are basically two ways it does so:

• Across some kind of membrane or barrier – for example, the stomach or intestinal mucosae after oral or rectal administration, the skin after topical administration, or the cells lining the airways after inhalation
• Directly into the vascular system after intravenous administration

Intramuscular and subcutaneous/intradermal injections are like a mixture of both because they create a depot of drug at the site of injection which is then absorbed into the blood stream.

Of course, the first barrier for drugs administered as a tablet or capsule is the step in which the product disintegrates and releases the drug. This might take a few minutes for tablets that disintegrate in the mouth, 30 – 60 minutes for plain tablets, or several hours for modified-release products designed to release the drug slowly. Absorption in the pharmacokinetic sense excludes this step because it’s a property of the formulation, not the drug itself.

Systemic absorption after intravenous administration is usually taken to be instantaneous. Any absorption step that involves a barrier increases the time required for the drug to reach the circulation. This is partly decided by the physicochemical properties of the drug molecule and the site where it is absorbed. For example, a highly soluble drug is quickly absorbed from the stomach; absorption via the skin takes several hours. Many other factors influence absorption, including gastric acidity, intestinal motility, interactions with other drugs or dietary components, and comorbidity.

For some drugs, there is an additional barrier between them and the circulation: the liver. Drugs are taken up from the blood by the liver and metabolised and, for some, this process – known as first pass metabolism– is both rapid and extensive and can mean that very little of a drug absorbed from the stomach or upper intestine reaches the systemic circulation intact (though its metabolites will, and they might be active or inactive). This effect is prominent after oral administration, but only for some drugs (examples include propranolol, glyceryl trinitrate and pethidine).

Distribution: Once in the circulation, the drug quickly spreads around the body in the blood. Where it goes again depends on its physicochemical properties.

• It may remain largely in the blood, in which case it may circulate as a free molecule or bound to plasma proteins. Examples include large proteins and drugs with high water solubility.
• It may diffuse into organs, the skin or fat or, given time, nails and bone. Drugs with high lipid solubility achieve high concentrations in adipose tissue and have low levels in the blood.
• Many drugs do not cross into the brain, which is protected by a layer of cells around brain capillaries known as the blood-brain barrier.

Distribution is another step that takes time. In fact, it may not be a single step and a drug can disappear from the blood quickly but take longer to build up stable concentrations in target organs and fat.

Metabolism: In general, drugs are broken down by enzymes into metabolites. These may have different pharmacokinetic and therapeutic properties from the parent molecule and can contribute to the drug’s therapeutic effects or cause side effects.

• These enzymes occur everywhere, including in the blood, skin and intestinal mucosae, but the major organ of metabolism for many drugs is the liver.
• The extent to which a drug is metabolised varies: some are almost unchanged, others almost entirely converted to metabolites.
• Metabolism in the liver is a common cause of drug interactions because drugs compete for the same enzymes, or they induce the synthesis of the enzymes that metabolise them. The result is that some drugs increase or decrease the metabolism of others and this can be a strong or a weak effect. Not all such interactions are clinically important but some are; details are always provided in the product’s Summary of Product Characteristics.

Rarely, a drug may be metabolised in the liver, excreted via the bile into the small intestine, converted back to the active molecule, then reabsorbed by the liver. This process, known as enterohepatic recirculation, occurs with oestrogens.

Elimination: There are two primary routes by which a drug (and its metabolites) are removed from the body: via the kidneys or the gastrointestinal tract. Both are usually quantitatively important for a drug and its metabolites, the proportions of each varying between drugs.

• Elimination via the kidneys is usually more therapeutically important because it depends largely on renal function, which is greatly affected by older age and comorbidities.
• Drugs are eliminated in faeces when they are not absorbed (or only partially so) or they are excreted into the gastrointestinal tract (e.g. from the liver via the biliary system).

 

Pharmacokinetic concepts

This section explains the common pharmacokinetic terms used in clinical practice. This information is provided for all medicines in the Summary of Product Characteristics (SPCs) though there may be little information available for older medicines.

Figure 1 shows the blood levels achieved after IV and oral administration of a single dose. The level after IV injection is higher but decreases relatively quickly. Oral absorption is slower and the peak level is lower, but medium-high levels are maintained for longer.

This difference is important because for many drugs a minimum blood level is needed to achieve a therapeutic effect (for some drugs, however, it’s the level in the target organ that’s important). Also, high blood levels are often associated with side effects (it’s not an all-or-nothing threshold: side effects become more likely as the blood level rises). Figure 2 shows where these levels are in relation to the blood levels after IV and oral administration. The area between the lines is the therapeutic range. As the figure shows, IV administration can briefly produce blood levels more likely to cause side effects, with only a short period within the therapeutic range. The time within the therapeutic range corresponds to the drug’s duration of action.

Why are the profiles of the blood levels so different after oral and IV administration? It’s because the processes of absorption, distribution, metabolism and elimination occur simultaneously. As soon as a drug appears in the blood, it starts to be distributed, metabolised and excreted. Up to the peak blood level (the maximum blood concentration, or Cmax), the rate of absorption outstrips the other processes; after, the combined effects of elimination are greater. These processes usually depend on the concentration of drug – so a higher concentration means their effect on the blood level is greater. IV administration delivers most of the dose very quickly but correspondingly large amounts are soon removed from the blood.

Note in the figure that the slope of the two lines is eventually the same. This is because the final rate of elimination from the blood due to metabolism and excretion is generally constant for a drug, regardless of how it is administered. This rate is clinically important because it determines how long the drug is present within the therapeutic range and therefore how often a dose must be given.

The final rate of elimination of a drug is measured by its half life (t_1/2), the time taken for its blood level to fall by half after the absorption and distribution phases are complete. Figure 3 illustrates how this relates to blood level after IV administration of a single dose of a drug with a half life of one hour: it takes an hour for the level to fall from 80 to 40, and another hour for it to fall to 20. After five half lives, the blood level is only about 3% of its maximum; its generally assumed that the level is clinically unimportant by this point.

Most drugs are given not as a single dose but in repeated doses over a long period. Provided the dose is repeated frequently (i.e. before the previous dose is substantially eliminated from the body), this results in a gradual increase in the blood level, which rises in a saw-tooth profile of peaksand troughs (Figure 4). The blood level eventually flattens off (plateaus) when the rates of absorption, distribution and elimination are balanced. This is called steady state. The time needed to reach steady state is about five half lives.

Some drugs take a long time time to reach steady state at the usual dose frequency. In such cases, it may be necessary to give a high loading dose at the start of treatment to achieve the therapeutic level more quickly. Conversely, some drugs cause side effects if they are given at the usual dose from the outset; it is then necessary to titrate the dose gradually until the optimum dose is reached. For drugs with a strong relationship between their blood level and their effects, the importance of half life is that it determines how frequently the dose has to be given (the dose interval) to maintain the blood level within the therapeutic range.

Other pharmacokinetic concepts

Some concepts in pharmacokinetics are derived mathematically from measurements of drug absorption, distribution and elimination. They do not exactly correspond to something that is directly measurable but they provide useful information about drug disposition.

Apparent volume of distribution (Vd): This theoretical concept is a measure of the extent to which a drug is distributed around the body; it is not an actual volume. Vd is equivalent to the volume of fluid that would contain the total amount of drug administered if it were to have the same concentration as in plasma. If a drug remained in the blood, its Vd would be the same as the total blood volume. If it was distributed into all body water, its Vd would be higher. If it was also distributed into fat or extensively bound to tissue, the Vd would be higher still. Vd usually has no direct clinical role but is useful in predicting blood levels from different doses. For example, a drug with a high Vd may need a loading dose to fully distribute the drug in the tissues before blood levels can begin to rise.

Area under the curve (AUC): This is another theoretical concept. It is an indication of the total exposure of the body to a drug. It is derived mathematically from the graph of blood level vs time (as in Figure 1) and provides a measure of the total amount of drug absorbed. It’s a useful concept when comparing similar drugs or formulations.

Bioavailability: This is the proportion of the administered dose that is systemically available to the body and it is calculated from the AUC. After intravenous administration, it’s assumed to be around 100%. After oral administration, it’s not the same as the total absorbed from the gastrointestinal tract because hepatic first pass metabolism means that a fraction of the dose is metabolised before reaching the systemic circulation. Some drugs have high bioavailability, some low; what’s more important is that enough can be absorbed systemically to achieve a therapeutic effect (provided that what’s left in the gastrointestinal tract has no further activity).

Clearance: The rate at which a drug is eliminated from the body is its total (or plasma)clearance(Cl). This represents the sum of the effects of metabolism and excretion. It is a mathematical concept, expressed as the volume of plasma from which drug is removed in a period of time. The total elimination by the kidneys or liver is defined by the renal clearanceand hepatic clearance.

Compartment: Figure 1 suggests that a drug is distributed and eliminated at one uniform rate, as if the body is a single compartment within which the drug is distributed. This is often an over-simplification and can lead to inaccuracy when working out the drug’s pharmacokinetics. There may be two or three distinct phases of distribution and elimination and, when trying to understand this mathematically, it is useful to imagine that the drug is moving between different compartments, each with its own pharmacokinetic characteristics. A drug is then said to have one, two- or three-compartment pharmacokinetics. These terms often appear in medical literature (including SPCs) but the concept is not directly important for routine clinical decision-making.

References 

Stephen H. Curry, Robin Whelpton. Drug Disposition and Pharmacokinetics: From Principles to Applications. 2011 John Wiley & Sons, Ltd.

Mark Tomlin. Pharmacology & Pharmacokinetics: A Basic Reader (Competency-based critical care). Springer Verlag London Ltd.

Jennifer Le. MSD Manual: Overview of Pharmacokinetics. http://www.msdmanuals.com/en-gb/professional/clinical-pharmacology/pharmacokinetics/overview-of-pharmacokinetics