Distribution
After absorption of drug from the site of administration into the systemic circulation, drugs must then distribute to tissues and organs, where they will then exert their therapeutic effects. The extent of drug distribution is dependent largely upon physicochemical properties of the drug, with more lipophilic drugs distributing more extensively than less lipophilic drugs. In contrast, the rate at which equilibriumis reached is dependent both upon the drug’s physicochemical properties and upon the vascular supply to the tissue, with equilibrium achieved most rapidly for a lipophilic drug distributing to tissues and organs with an extensive blood supply.
A lipophilic drug that distributes into highly-perfused tissues but not into less-well-perfused tissues to any appreciable degree would achieve complete distribution very rapidly and would be expected to show one-compartment kinetic behaviour after an IV bolus dose. This behaviour may also be observed following administration of an IV bolus dose of a very hydrophilic drug that remains almost entirely in the plasma and that does not distribute beyond the plasma to any significant degree. When an appreciable proportion of an administered drug distributes more slowly into some tissues or organs – most likely organs with a more limited blood supply – the distribution phase is not yet complete when we start taking plasma samples from the patient. We can see evidence of distribution (which is a first-order, concentration-dependent process) occurring simultaneously with elimination (which is also a first-order, concentration-dependent process), as the blade of the hockey-stick curve on a semi-logarithmic plot. This is consistent with two-compartment kinetic behaviour.
When drug is removed from blood, by hepatic or renal clearance, drug from tissues redistributes back into the blood to re-establish the equilibrium (as predicted by Le Chatelier’s principle). For a one-compartment drug, this redistribution is very rapid and it has little effect on the rate at which drug is cleared from the plasma. But for a two-compartment drug, the slower redistribution of drug from those tissues that make up the tissue compartment causes overall elimination from the central compartment to occur more slowly than would be the case if drug could return from the tissue compartment to the central compartment at an unlimited rate. This tends to reduce the value for clearance, and the β rate constant for loss of drug from the entire volume of distribution during the terminal elimination phase is smaller than the theoretical first order elimination rate constant (kel) would be for loss of drug from a single compartment of identical volume. Click here to view a short vodcast explaining why these elimination rate constants differ.
