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

Pharmacokinetics 811

very rapidly into the circulation and bypass the first-pass III. DRUG DISTRIBUTION
effect of the liver. Aerosols with sizes greater than 10
µm are often trapped in the nasal passages or the phar- Once a drug enters the circulation of an organism, the drug
ynx and upper airway. Therapeutic aerosols, such as those is mixed with the fluid circulating through the body. After
used for acute obstructive asthma, need to be designed absorption of a drug into the bloodstream, it is simulta-
to deliver particles less than 10 µm. There is a clear ad- neously distributed throughout the body and eliminated.
vantage of direct delivery to the lungs in the treatment of In mammals such as humans, the circulation consists of
pulmonary disease in that many side effects of the drugs the arteries, veins, and the heart. The lymphatic circula-
which might occur if they were administered systemically tion represents a third circulation, which returns proteins,
can be avoided. salts, and fluid from the interstitium to the venous circu-
lation; the flow rate in this system is slow relative to the
blood and is therefore less important for low-molecular
weight substances which rapidly transport across blood
E. Mathematical Approaches to
endothelia. However, the lymphatics can be significant in
the Description of Absorption
the recirculation of high-molecular weight solutes in the
and Bioavailability
body; the daily flow through the thoracic duct amounts to
The definition of bioavailability given above includes ele- 1–2 plasma volumes per day.
ments of the rate of drug entry into the target compartment The distribution phase within the central volume of dis-
as well as the total amount. Let us assume that the blood tribution V d is usually assumed to be very short relative
circulation is the target compartment and that i.v. admin- to the half-life of the drug t 1/2 . Unbound, highly lipid-
istration is the standard route to which all others must be soluble medications cross cell boundaries rapidly and may
compared. Then F may be calculated as the ratio of the be quickly metabolized by the liver or distributed to fat.
area under the plasma concentration versus time curve of Medications which are highly bound (>99%) may be re-
the test drug (or route) to that of the standard when equal stricted to the vascular space but may have a large apparent
doses are administered: volume of distribution. Most water-soluble medications,
either unbound or partially bound, are distributed rapidly
AUC test route viathecirculationtoallregionsofthebodyand,depending
F = , (9)
on the nature of the endothelial barrier, transport to some
AUC iv
degree into the extravascular space of tissue. The drug
where AUC is the area under the plasma concentration may transport from the extravascular space into a cell;
versus time curve. If repeated doses are given, F can be it may be bound locally; or it may undergo recirculation
calculated from the ratio of the steady-state concentrations to the vascular space, where it will undergo distribution
C ss which result from the same dose being given via the again or be eliminated via several mechanisms discussed
test route and i.v.: below. Data concerning binding, volume of distribution,
and mechanism of elimination on many drugs are tabu-
C ss,test
F = . (10) lated in useful, pocket-sized references which are listed in
the Bibliography.
C ss,iv
There may exist other compartments which exchange
Actual rates of transfer across biological barriers are gen- with the central circulation which are not well perfused but
erallycalculatedfromEqs.(5)and(6).Tocalculatetherate must be accounted for in modeling the kinetics of a drug
coefficients of either equation, data consisting of concen- (see Fig. 6). Muscle in a recumbent, resting human is rel-
tration and volume versus time in both the compartment atively poorly perfused compared to the liver or kidney.
in which the drug is administered and in the receiving General expansion of the muscle interstitium is termed
compartment are required. If the target compartment is edema and can significantly alter the magnitude of V d in
the circulation, venous concentrations may be the only the case of intensive care unit patients who have received
data available. In this case, the rate of transfer can be ex- massive amounts of intravenous fluids. In certain other
pressed as the product of the plasma concentration and the pathologic conditions, the extravascular space of patients
volume of distribution divided by the total dose adminis- may undergo extensive local increases and form so-called
tered. This produces a fractional rate of absorption defined “third spaces.” In the pleural space, this is called a pleu-
by ral effusion; in the peritoneal cavity, the fluid is termed
ascites; fluid around the heart is termed a pericardial ef-
C plasma V d fusion. Each of these fluid collections forms a compart-
fractional rate of absorption = . (11)
dose × time ment which can exchange with the normal extracellular