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Section IBasic principlesDefinition and measurement of pharmacokinetic parameters
The parameters described in the compartmental models are useful for comparing
the persistence of different drugs in the body namely: volume of distribution (Vd),
clearance (Cl) and time constants (τin the single compartment andα,βandγin
multi-compartment models). Half-lives (t1/2)arerelated to their corresponding time
constants by a factor of ln(2), which is 0.693.Volume of distribution
Volume of distribution (Vd) is defined as the apparent volume into which a drug
disperses in order to produce the observed plasma concentrations. It does not cor-
respond to any particular physiological volume and can be much larger than total
body water. The physicochemical properties of a drug including its molecular size,
lipid solubility and charge characteristics all influence the volume of distribution.
Propofol is a very lipid-soluble drug and has a large volume of distribution of about
250 litres; pancuronium is a highly charged molecule and has a relatively small vol-
ume of distribution of about 17.5 litres. Tissue binding of drug, particularly intracel-
lular sequestration, can account for extremely high volumes of distribution; the anti-
malarial chloroquine has a volume of distribution in excess of 10,000 litres. Pathology
also influences the kinetic parameters; in hepatic and renal disease volumes of dis-
tribution are increased as the relative volumes of body fluid compartments change.
Inthe simple one-compartmental model, Vd is a constant that relates dose admin-
istered to the plasma concentration at time zero. It has the units of volume (e.g. litres)
but can be indexed to bodyweight and expressed as litres.kg−^1 .Inthe simple model,
Vd is the initial dose divided by the plasma concentration occurring immediately
after administration:
Vd=dose/plasma concentration=X/C 0.
Inthe multi-compartment models, the central compartment volume is the initial
volume into which the drug disperses (Vintial). The volume of this compartment
depends partly on the degree of protein binding; a highly protein bound drug will
have a larger central compartment volume than a drug that is poorly bound. Propofol
is 98% protein bound and has a central compartment volume of about 16 litres,
compared with an actual plasma volume of about 3 litres. The volume of this central
compartment can be estimated from the rapid distribution phase; if the dose given
was X and the intercept on the y-axis is A then:
Vintial=X/A.
The total volume of distribution is the sum of all the volumes that comprise the model.
There are several methods available that attempt to estimate this volume: Vextrap,
Vareaand Vss.The first of these simply ignores the contribution made by any volume
apart from that associated with the terminal phase of elimination; the intercept
of the line representing terminal elimination is extrapolated back to its intercept