Clinical pharmacokinetics

Clinical pharmacokinetics

Pharmacokinetics can be simply described as the study of 'what the body does to the drug' and includes: 
•    the rate and extent to which drugs are absorbed into the body and distributed to the body tissues
•    the rate and pathways by which drugs are eliminated from the body by metabolism and excretion
•    the relationship between time and plasma drug concentration.

Understanding these processes is extremely important for prescribers because they form the basis on which the optimal dose regimen is chosen and explain the majority of the inter-individual variation in the response to drug therapy.

Four phases of pharmacokinetics

The main processes involved in pharmacokinetics are absorption, distribution, and the two routes of drug elimination, metabolism and excretion. Together they are sometimes known by the acronym ‘ADME’. Distribution, metabolism and excretion are sometimes referred to collectively as drug disposition.

Absorption is the process by which drugs enter the body. Given by any route other than intravenously, drug molecules must cross tissue membranes (e.g. skin epithelium, subcutaneous tissue, gut endothelium, capillary wall) to enter the blood.

Distribution is the process by which drugs move around the body. After entering the blood, drug molecules must cross capillary walls to enter the tissues, reach cell membranes and enter cells.

Metabolism is the process by which drugs are chemically altered to make them sufficiently water-soluble for excretion in urine or faeces (via the biliary tract). Metabolism occurs in a variety of body organs and tissues, but chiefly in the liver, gut wall, kidney and skin.

Excretion is the process by which drugs leave the body. Drugs that are sufficiently water-soluble will be excreted unchanged in the urine. Lipid-soluble drugs must be modified to water-soluble metabolites before excretion via the kidney or into the intestine via the bile.

Drug absorption

Absorption is the process by which drug molecules gain access to the bloodstream from the site of drug administration. The speed of this process (the rate of drug absorption) and its completeness (the extent of drug absorption) depend on the route of administration.

Routes of administration can be considered in two categories:

Enteral. Drugs given by mouth are normally swallowed before being absorbed in the stomach or small bowel, after which they enter the portal venous system and pass through the liver before gaining access to the systemic circulation. Some drugs introduced into the alimentary tract are absorbed directly into the systemic circulation without passing through the liver (e.g. via the buccal, sublingual or rectal routes), thereby avoiding the potential hazards of gastric acid, binding to food, and metabolism by gut wall or liver enzymes (first-pass metabolism).

Parenteral. This includes any route that avoids absorption via the gastrointestinal tract such as administration by injection, inhalation or by application to the skin.

Absorption after an oral dose is a lengthy process, during which drug molecules may be damaged (e.g. denatured by gastric acid), sequestered (e.g. bound to food preventing absorption) or modified by first-pass metabolism. As a consequence of all these hazards, it is not surprising that absorption is frequently incomplete following oral administration. The proportion of a dose that reaches the systemic circulation unscathed is known as the bioavailability of the drug.

Further information is provided in the general Pharmacology section under Drug absorption.

Drug metabolism

Metabolism is the process by which drugs are chemically changed from a lipid-soluble form suitable for absorption and distribution to a more water-soluble form that is suitable for excretion. The process effectively eliminates the parent drug.

Drug metabolism occurs in two phases:

Phase I – in which drug molecules are altered chemically (by oxidation, reduction or hydrolysis) to make them suitable for Phase II reactions or for excretion. Oxidation is much the commonest form of Phase 1 reaction and involves chiefly members of the cytochrome P450 family of membrane-bound enzymes in the smooth endoplasmic reticulum of the liver cells. Most products of Phase 1 metabolism are pharmacologically inactive, although some retain activity to a greater or lesser degree, while others have activity that the parent drug did not possess.

 

Phase II – in which molecules of Phase I metabolite (or in some cases, unchanged drug) combine with an endogenous substrate  to form an inactive conjugate that is much more water-soluble than the Phase I metabolite. Phase II reactions include synthesis of glucuronide or sulphate products, acetylation or methylation, and conjugation with glutathione.

The rate of drug metabolism varies widely between individuals, influenced by genetic and environmental factors. This is the major reason for inter-individual differences in the plasma concentration of some drugs after a standard dose, which leads to wide variation in drug response.

Further information is provided in the general Pharmacology section under Drug metabolism.

Drug excretion

Excretion is the process by which drugs and their metabolites are removed from the body. They may leave in excreted fluids (chiefly urine and bile), solids (faeces) or gases (expired air).

Urinary excretion is the usual route of elimination for low-molecular-weight drugs that are not metabolised and are sufficiently water-soluble to avoid reabsorption from the renal tubule. Small water-soluble metabolites that enter the bloodstream after metabolism in the liver or other organs are also excreted via this route. Drugs bound to plasma proteins are not filtered by the glomeruli, but small molecules that are free are filtered and enter the tubules, where they may be reabsorbed if they are still lipid-soluble, but not if they are water-soluble. 

Faecal excretion is the preferred route of elimination for larger molecular-weight drugs, including those that are conjugated with glucuronide in the liver, and any drugs that are not absorbed. Molecules of drug or metabolite that enter the bile after liver metabolism are carried into the intestinal lumen, pass down the gut and are eliminated in the faeces. If they are still sufficiently lipid-soluble, some molecules of unchanged drug or metabolite may be reabsorbed and re-enter the portal vein (Fig 9). This recycling between the liver, bile, gut and portal vein is known as the entero-hepatic circulation.

Further information is provided in the general Pharmacology section under Drug excretion.

Concentration-time relationships

After administration a drug is immediately subject to absorption and distribution, both of which occur relatively quickly, followed by a longer period during which the drug is eliminated. These phenomena can be described by plotting the concentration of the drug in plasma against the time that has elapsed since administration. These concentration-time relationships show some important differences between drugs. Some are eliminated by first order kinetics (a constant fraction of the drug is removed over a given time), and some are zero-order (a constant amount of drug is removed over a given time). Most drugs are eliminated by first-order kinetics and their concentration over time can be predicted by knowing their half-life, the period over which concentration halves. The concentration-time relationship also varies depending on the route of administration. It demonstrates clearly how the exposure to the pharmacological effects of a drug over time (its bioavailability) is significantly less when it is given by the oral compared to the intravenous route.

 

Repeated drug dosing

Most drugs are effectively removed from the body in the hours and days after administration by metabolism and excretion. This means that prescribers have to plan repeated administration of doses if they wish to ensure that the drug concentrations at the site of action remains effective. The pharmacokinetic characteristics of individual drugs will determine the frequency of these doses, how long prescribers will have to wait before repeated doses achieve a plateau (steady state) concentration, and how long it will take for the drug to disappear after treatment is stopped. The pharmacokinetics also explains why some drugs with short half-lives have to be given continuously by intravenous infusion and others with long half-lives require loading doses to hasten their clinical effects.