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Encyclopedia of Physical Science and Technology EN011J-559 July 25, 2001 18:57

Pharmacokinetics 807

FIGURE 2 Pharmacokinetics: an expanded definition of the three phases of drug delivery to the site of action.

for t 1/2 is the same for drugs which have more complex C. Bioavailability
curves of concentration versus time or are administered
The bioavailability F of a drug is equal to the fraction of
via a route other than the intravenous (i.v.) route. However,
drug which absorbed unchanged into the target compart-
the method of calculation may differ from the relatively
ment. For example, drugs which are injected intravenously
simple arrangement of Eq. (1). Various texts listed in the
into mammals have a bioavailability of 1 because all of
Bibliography give more complex formulations.
the drug arrives in the plasma, which distributes it to other
Drug clearance Clr is analogous to creatinine clearance
parts of the body. If other routes are used to administer the
andisequaltothevolumeofdistribution V d clearedofdrug
drug,suchastheoralroute, F willbedeterminedbyitsrate
per unit time:
and extent of absorption from the stomach and intestines.
Clr = k elim V d . (2) Specific routes of absorption will be discussed below.
D. Mechanisms of Transport
B. Volume of Distribution
Drugs pass across barriers by a number of mechanisms.
The apparent volume of distribution V d is equal to the dose
Passive mechanisms utilize the forces of concentration dif-
given in an i.v. bolus divided by the plasma (or blood)
ferences or pressure differences to move substances from
concentration at time zero, C 0 . The value of C 0 can be
one site to another. Active transport of a drug is typically
found by the extrapolation of the plasma concentration
via a specific transporter, requires energy, and moves so-
curve back to time zero, as shown in Fig. 3. An alternate
lute against its electrochemical gradient. Figure 4 illus-
method of calculation is
trates these definitions.
i.v dose (or dose absorbed) Most drugs cross membranes via the passive processes
V d = . (3)
area under plasma curve × k elim of diffusion or convection. Diffusion is the process by
which a substance moves from a region of high concen-
The apparent volume of distribution does not necessarily
tration to one of low concentration and is important for
correspond to any anatomic compartment in the body
movement of low-molecular weight substances (MW <
but is a “virtual” compartment which is mathematically
6000 Da). The governing mathematical expression is
defined by equations such as (3). For example, if a drug
such as morphine is bound to protein and tissue, the dC
rate of diffusion =−DA . (4)
volume of distribution is several times the total body dx
water volume, which is approximately 60% of the body In this equation D is the diffusion coefficient, which
weight (for morphine V d = 3.5 L/kg of body weight or depends on the molecular size of the substance, its lipid
∼6 L/L body water). solubility, the ionic charge, and the characteristics of the