Why Does Drug Concentration Decline Over Time? - Introduction
Fig 1 Diagram showing the major pharmacokinetic processes that influence changes in drug concentration in the hours after administration. Most drugs are administered orally and are absorbed from the gut to reach the liver via the portal circulation. The proportion of the drug that isn't lost to 'first-pass metabolism' reaches the systemic circulation and is distributed around the body. Drug molecules present in the systemic circulation become vulnerable to elimination as they pass through the liver (metabolism and excretion via bile) and kidneys (excretion). All of an intravenous dose reaches the systemic circulation and is immediately available for distribution and elimination.
Fig 2 Graph of plasma drug concentration (logarithmic scale) against time after an intravenous dose. For drugs that are rapidly distributed into a single compartment from which they are subsequently eliminated the graph would contain a simple straight line slope. The fact that this graph shows two slopes indicates that there is a distribution phase as drug moves out into a second peripheral compartment before an equilibrium is reached throughout the whole volume of distribution. At that point elimination occurs steadily from the central compartment. a and b are the rate constants of distribution and elimination respectively. C0 is the extrapolated concentration at time zero that would have occurred if the drug had been instantaneously distributed into its complete volume of distribution (Vd).
The processes of drug distribution and elimination begin as soon as drug molecules enter the body (Fig 1)
. After an intravenous dose, this is immediate, whereas after administration by other routes there is a delay while the drug is absorbed from the tissue into which it has been injected (or to which it has been applied) or from the lumen of the gastrointestinal tract.
Drugs must be lipid-soluble to be absorbed into the body and distributed around it but will generally need to be rendered more water-soluble by metabolism before they can be eliminated in the urine or faeces. Processes exist to eliminate all drugs, so the amount of drug in the body falls progressively with time after dosing.
The amount of drug in the body (A) at any time after dosing cannot be measured, only estimated by relating the measured plasma concentration of the drug (C) to the drug's known apparent volume of distribution (Vd), using the equation:
A = Vd.C
For most drugs, the body can be thought of as a two-compartment model, and so drug molecules are not instantly distributed throughout the apparent volume of distribution; the process of distribution from the plasma and well-perfused organs to less well-perfused tissues takes time. For this reason, judged from a graph of plasma concentration against time (Fig 2) the rate of elimination cannot be seen until distribution is complete.
