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Basic pharmacokinetic parameters

Created: 5/4/2004
Updated: 6/2/2008

The pharmacokinetic behaviour of most drugs can be summarised by the parameters listed below. The parameters are constants, although their values may differ from patient to patient, and in the same patient under different conditions.

Bioavailability expresses the extent of drug absorption into the systemic circulation. The absorption rate constant expresses the speed of absorption. These parameters influence the maximum (peak) concentration, the time at which the maximum concentration occurs (peak time) and the area under the concentration-time curve (AUC) after a single oral dose. During long-term drug therapy, the extent of absorption is the more important measurement because average concentration depends on it; the degree of fluctuation is related to the absorption rate constant.

The apparent volume of distribution is the amount of fluid that would be required to contain the drug in the body at the same concentration as in the blood or plasma. It can be used to estimate the dose required to produce a given concentration and the concentration expected for a given dose. The unbound concentration is closely associated with drug effects, so unbound fraction is a useful measure, particularly when plasma protein binding is altered --e.g. by hypoalbuminaemia, renal or hepatic disease or displacement interactions. The apparent volume of distribution and the unbound fraction in plasma are the most widely used parameters for drug distribution.

The rate of elimination of a drug from the body varies with the plasma concentration. The parameter relating elimination rate to plasma concentration is total clearance, which equals renal clearance plus extrarenal (metabolic) clearance. 

The fraction excreted unchanged helps to assess the potential effect of renal and hepatic diseases on drug elimination. A low fraction indicates that hepatic metabolism is the likely mechanism of elimination and that hepatic disease may therefore affect drug elimination. Renal diseases produce greater effects on the kinetics of drugs with a high fraction excreted unchanged.

The extraction rate of a drug from the blood by an eliminating organ, such as the liver, cannot exceed the rate of drug delivery to the organ. Thus, clearance has an upper limit, based on drug delivery and hence on blood flow to the organ. Furthermore, when the eliminating organ is the liver or gut wall, and a drug is given orally, part of the dose may be metabolised as it passes through the tissues to the systemic circulation; this process is called first-pass metabolism. Thus, if extraction (clearance) of a drug is high in the liver or gut wall, oral bioavailability is low, sometimes precluding oral administration or requiring an oral dose much larger than an equivalent parenteral dose. Drugs with extensive first-pass metabolism include alprenolol, hydralazine, isoproterenol, lidocaine, meperidine, morphine, nifedipine, nitroglycerin, propranolol, testosterone and verapamil.

The elimination rate constant is a function of how a drug is cleared from the blood by the eliminating organs and how the drug distributes throughout the body.

Half-life (elimination) is the time required for the plasma drug concentration or the amount of drug in the body to decrease by 50%. For most drugs, half-life remains the same, regardless of how much drug is in the body. Exceptions include phenytoin, theophylline and heparin.

Mean residence time (MRT), another measure of drug elimination, is the average time a drug molecule remains in the body after rapid IV injection. Like clearance, its value is independent of dose. After an IV bolus,

AUMC is the area under the first moment of the plasma concentration-time curve. For a drug with one-compartment distribution characteristics, MRT equals the reciprocal of the elimination rate constant.

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