DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

percentage of the administered dose. Values represent
the percentage expected in a healthy young adult (creatinine
clearance ≥100 mL/min). When possible, the
value listed is that determined after bolus intravenous
administration of the drug, for which bioavailability is
100%. If the drug is given orally, this parameter may
be underestimated due to incomplete absorption of the
dose; such approximated values are indicated with a
footnote. The parameter obtained after intravenous dosing
is of greater utility because it reflects the relative
contribution of renal clearance to total body clearance
irrespective of bioavailability.
Renal disease is the primary factor that causes
changes in this parameter. This is especially true when
alternate pathways of elimination are available; thus, as
renal function decreases, a greater fraction of the dose
is available for elimination by other routes. Because
renal function generally decreases as a function of age,
the percentage of drug excreted unchanged also
decreases with age when alternate pathways of elimination
are available. In addition, for a number of weakly
acidic and basic drugs with pK a
values within the normal
range for urine pH, changes in urine pH will affect
their rate or extent of urinary excretion (see Chapter 2).
Binding to Plasma Proteins. The tabulated value is the
percentage of drug in the plasma that is bound to
plasma proteins at concentrations of the drug that are
achieved clinically. In almost all cases, the values are
from measurements performed in vitro (rather than
from ex vivo measurements of binding to proteins in
plasma obtained from patients to whom the drug had
been administered). When a single mean value is presented,
it signifies that there is no apparent change in
percent bound over the range of plasma drug concentrations
resulting from the usual clinical doses. In cases in
which saturation of binding to plasma proteins is
approached within the therapeutic range of plasma drug
concentrations, a range of bound percentages is provided
for concentrations at the lower and upper limits of
the range. For some drugs, there is disagreement in the
literature about the extent of plasma-protein binding; in
those cases, the range of reported values is given.
Plasma-protein binding is affected primarily by
disease states, notably hepatic disease, renal failure, and
inflammatory diseases, that alter the concentration of
albumin, α 1
-acid glycoprotein, or other proteins in
plasma that bind drugs. Uremia also changes the binding
affinity of albumin for some drugs. Disease-induced
changes in plasma-protein binding can dramatically
affect the volume of distribution, clearance, and elimination
t 1/2
of a drug. In regard to clinical relevance, it is
important to assess the change in unbound drug concentration
or AUC, particularly when only unbound
drug can cross biological barriers and gain access to the
site of action.
Plasma Clearance. Systemic clearance of total drug from
plasma or blood (see Equations 2–5 and 2–6) is given
in Table AII–1. Clearance varies as a function of body
size and, therefore, most frequently is presented in
the table in units of mL/min/kg of body weight.
Normalization to measures of body size other than
weight may at times be more appropriate, such as normalization
to body surface area in infants to better
reflect the growth and development of the liver and kidneys.
However, weight is easy to obtain, and its use
often offsets any small loss in accuracy of clearance
estimate, especially in adults. Exceptions to this rule
are the anticancer drugs, for which dosage normalization
to body surface area is conventionally used. When
unit conversion was necessary, we used individual or
mean body weight or body surface area (when appropriate)
from the cited study, or if this was not available,
we assumed a body mass of 70 kg or a body surface
area of 1.73 m 2 for healthy adults.
In some cases, separate values for renal and nonrenal
clearance are also provided. For some drugs, particularly
those that are excreted predominantly
unchanged in the urine, equations are given that relate
total or renal clearance to creatinine clearance (also
expressed as mL/min/kg). For drugs that exhibit saturation
kinetics, K m
and V max
are given and represent,
respectively, the plasma concentration at which half
of the maximal rate of elimination is reached (in units
of mass/volume) and the maximal rate of elimination
(in units of mass/time/kg of body weight). K m
must
be in the same units as the concentration of drug in
plasma (C p
).
Intrinsic clearance from blood is the maximal
possible clearance by the organ responsible for elimination
when blood flow (delivery) of drug is not limiting.
When expressed in terms of unbound drug, intrinsic
clearance reflects clearance from intracellular water.
Intrinsic clearance is tabulated for a few drugs. It also
is mathematically related to the biochemical intrinsic
clearance [V max
/(K m
+ C)] determined in vitro. In almost
all cases, clearances based on plasma concentration
data are presented in Table AII–1, because drug analysis
most often is performed on plasma samples. The few
exceptions where clearance from blood is presented are
indicated by footnote. Clearance estimates based on
blood concentration may be useful when a drug concentrates
in the blood cells.
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APPENDIX II
DESIGN AND OPTIMIZATION OF DOSAGE REGIMENS: PHARMACOKINETIC DATA