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

Pharmacokinetics 813

for large amounts of fat in a body when calculating Age, sex, and disease states such as hepatic cirrhosis,
the LBM: renal failure, and congestive heart failure affect drug bind-
ing and distribution. These will be discussed below.
LBM obesity = IBW + 0.3(TBM − IBW). (14)
In some cases, the postsurgical or septic patient will be- IV. DRUG METABOLISM
come severely edematous and take on 10–20Lof fluid. AND ELIMINATION
Since this expansion occurs chiefly in the extracellular
space, drugs will distribute to the edematous space. This
As illustrated in Fig. 2, once a drug is absorbed and dis-
additional weight must be added to the IBW, which can be
tributed, it will enter the elimination phase. It may be re-
estimated from the patient’s height, or alternatively, can be
moved directly by the kidney and appear unchanged in
added to the LBM calculated from the admission height
the urine. Or it can be taken up by the liver or another
and weight.
organ and metabolized to secondary products, which are
secreted into the biliary system or are cleared by the kid-
ney. If the patient is in renal failure, some form of renal
B. Binding
replacement therapy will be initiated, and drug circulating
There is typically a large difference between the apparent in the plasma will be cleared to the dialysate according to
volumeofdistribution, V d ,andtheactualanatomicvolume the degree of plasma binding and the molecular size of the
which contains the drug, V anat . The volume V anat cannot free drug.
exceed the total body water, which is equal to approxi-
mately 60% of the lean body mass. The total body water A. Renal Excretion
is approximately two-thirds intracellular and one-third ex-
tracellular. The extracellular space is further divided into Approximately 20% of the cardiac output circulates
intravascular (7–8% of LBM, with the plasma taking up through the kidneys. As the blood passes through each
4–5% and the red cells taking up the rest) and extravascu- glomerulus, a portion is filtered at the glomerular filtration
lar space (11–12% of the LBM). A drug with no binding rate (GFR). GFR decreases with age, and can be estimated
will have V d which matches one of these volumes. A drug from the Cockcroft–Gault relationship:
which is highly bound to plasma proteins (>99%) may
(140 − age) × IBW(kg)
have an apparent volume of distribution many times its GFR men = . (15)
72 × serum creatinine (mg/dl)
actual volume of distribution, which would approximate
the intravascular space. The GFR women is found by multiplying Eq. (15) by 0.85.
Binding to plasma proteins usually restricts movement IBW is defined by Eqs. (13a) and (13b); age is in years;
of the drug out of the vasculature. Since albumin is the serum creatinine is measured. Solutes of low molecular
most important protein with respect to binding, states of weight (<6000 Da) which are not bound to protein are fil-
altered serum albumin concentrations, such as pregnancy, tered at the same rate as plasma water. Larger molecules or
liver dysfunction, or the nephrotic syndrome, can change those bound to proteins will pass through the glomerulus at
the free plasma concentration of a highly bound drug and a slower rate than the GFR. Macromolecules with anionic
significantly influence the distribution and elimination of charges are further restricted in their passage through the
a drug. α 1 -Acid glycoprotein is another important binding normal glomerulus when compared with molecules with
protein for basic drugs. Its molecular weight is 40,000 Da neutral or positive charges. The glomerular filtrate in the
and it will therefore pass through the capillary endothe- tubule is further modified in the proximal tubule by reab-
lium. Since it is an acute-phase reactant, its concentration sorption or secretion of substances. Diuretic medications
in plasma increases with states of inflammation or cancer such as hydrochlorothiazide, furosemide, and amiloride
but falls with pregnancy or nephrosis. Other proteins play are secreted in the proximal tubule and act on transporters
a minor role in drug binding. located on the apical side of the tubule further along in the
In addition to plasma proteins, cellular elements and nephron.
tissues bind drugs. For example, it has been demon- For a drug whose transport is not limited by renal blood
strated that significant amounts of acetazolamide, pheny- flow, the following expression can be used to calculate
toin, propanolol, and quinidine are taken up in red blood renal clearance (Clr kidney ):
cells. Drug binding to tissues is important but poorly un-
Clr kidney = f d (GFR + Clr KS )(1 − f R ), (16)
derstood, with the chief effect being on the time course of
the drug. A decrease in tissue binding results in a decrease where f d is the free drug fraction in blood, Clr KS is the rate
in the half-life of the drug. of renal tubular secretion of drug, and f R is the fraction