Pharmacokinetics (PK) is a branch of pharmacology that studies, both mathematically and descriptively, how the body affects a drug after administration, through the processes of absorption, distribution, metabolism, and excretion. In simplest terms, it can be described as what the body does to the drug.
Pharmacokinetic concepts are used during drug development to determine the optimal formulation of a drug, dose (along with effect data), and dosing frequency. For drugs with a wide therapeutic index (difference between the minimum effective dose and the minimum toxic dose), knowledge of the drug’s pharmacokinetic properties in that individual patient may not be particularly important. For example, nonsteroidal anti-inflammatory drugs, such as ibuprofen, have a wide therapeutic index, and thus knowledge of the pharmacokinetic parameters in a given individual is relatively unimportant since normal doses can vary from 400 to 3200 mg per day with no substantial difference in acute toxicity or effect. However, for drugs with a narrow therapeutic index, knowledge of that drug’s pharmacokinetic profile in an individual patient has paramount importance.
If there is little difference between the minimum effective dose and the toxic dose, slight changes in a drug’s pharmacokinetic profile, or even simply interindividual differences, may require dosage adjustments to minimize toxicity or maximize efficacy. For example, the blood concentrations of the antiasthmatic drug theophylline must usually be maintained within the range of 10–20 g/mL. At concentrations below this, patients may not obtain relief of symptoms, while concentrations above 20 g/mL can result in serious toxicities, such as seizures, arrhythmias, and even death.
Thus, a drug’s pharmacokinetic profile may have important clinical significance beyond its use in drug development.
Within the body, drugs undergo several changes. From start to finish, the biological changes consist of four drug processes – absorption, distribution, metabolism, and excretion (abbreviated ADME). Absorption and distribution determine how quickly a drug molecule reaches its site of action. If after reaching the site of action and nothing happens to the drug, its effect will continue indefinitely. This may be dangerous to the body. The action of the drug in the body is terminated by the process of metabolism and elimination.
Distribution, metabolism, and excretion phases are sometimes referred to collectively as drug disposition.
Absorption is the passage of a substance through a membrane into the bloodstream. 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 bloodstream from where it is carried to its site of action.
The rate at which a drug reaches its site(s) of action depends partly on its rate of absorption. Absorption rate in turn depends on the rate of translocation of the drug across specific barriers interposed between the sites of administration and action. The route of drug administration determines the number of these interposed barriers and hence influences the rate of absorption.
Following absorption, drug molecules move from the bloodstream into the tissues and fluids of the body. This process is known as distribution. The total body area or body fluid to which a drug is distributed is known as the volume of distribution. Since drugs are distributed by way of the bloodstream, the amount of drug distributed to any body tissue or organ depends partly on the blood flow to that system. Thus, organs like the liver, kidneys, and the brain which are more rapidly perfused will in principle have higher concentration of any drug when compared to less perfused tissues like the muscles.
Some drugs do not pass well through cell membranes with very small passages, such as those covering the placenta and the brain. These are referred to as placental and blood-brain barriers, although the barrier is not a complete barrier because some drugs and some conditions make it possible for drugs to easily pass through these areas. Individual patient variation can greatly affect the amount of drug that is distributed.
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 of drugs occurs in a variety of body organs and tissues, but chiefly in the liver, gut wall, kidney, and skin. Few drugs are destroyed or inactivated by gastric enzymes.
Metabolism of drugs results, in most cases, to less active metabolites or products. However, some drugs are metabolized to active or even more active metabolites (e.g., codeine to morphine).
There is individual variation in the rate with which drugs are metabolized. In some individuals, the rate of metabolism is so quick that their serum and tissue concentrations become therapeutically inadequate after a normal dose. In others, the rate of metabolism may be so slow that ordinary doses can accumulate to toxic levels.
Excretion is the process by which waste products of drug metabolism are removed from 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.
When excretion of drug is impaired (especially those that are removed unchanged), the dosage or the frequency of administration has to be reduced. Failure to do so may result in the accumulation of the drug, which in turn may lead to toxic effects. Some drugs can block or promote the renal excretion of other drugs, causing them to accumulate and enhance their effects (e.g., probenecid blocks renal excretion of penicillins) or causing them to be rapidly excreted and so diminish their effects.