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

1892 has been selected from the literature, based on the scientific
judgment of the authors. Most data are in the
form of a study population mean value ± 1 standard
deviation (mean ± SD). However, some data are presented
as mean and range of values (in parentheses)
observed for the study population (i.e., the lowest and
highest value reported). There are times when data are
reported as a geometric mean with a 95% confidence
interval. If sufficient data were available, we presented
a range of mean values obtained from different studies
of similar design in parentheses, sometimes below the
primary study data. Occasionally, only a single mean
value for the study population was available in the literature
and is reported as such. Finally, some drugs can
be administered intravenously in an unmodified form
and orally as a prodrug. When relevant information
about both the prodrug and the active molecule are
needed, we have included both, using an abbreviation to
indicate the species that was measured, followed by
another abbreviation in parentheses to indicate the
species that was dosed [e.g., G (V) indicates a parameter
for ganciclovir after administration of the prodrug,
valganciclovir].
A number of recently approved drugs are actually
the active metabolite or stereoisomer of a previously
marketed drug. For example, desloratadine is the
O-desmethyl metabolite of loratadine, and esomperazole
is the active S-enantiomer of omeprazole. Unless
the parent drug and the active metabolite offer distinct
therapeutic advantages, only the more established or
more commonly used drug is listed, and relevant information
on its alternate active form is presented in the
same table. This approach has permitted us to include
more drugs in the Appendix, hopefully without undue
confusion. The only exception is with prednisone and
prednisolone, which undergo interconversion in the
body.
Unless otherwise indicated in footnotes, data
reported in the table are those determined in healthy
adults. The direction of change for these values in particular
disease states is noted below the average value.
One or more references are provided for each of the
established drugs, typically an original journal publication,
a review on its clinical pharmacokinetics, or webbased
drug database; the latter two secondary sources
provide a broader range of papers for the interested
reader. In some instances, we have relied on unpublished
data provided by the drug sponsor in its New
Drug Application (NDA) files or package labeling submitted
to the U.S. Food and Drug Administration
(FDA).
APPENDIX II
DESIGN AND OPTIMIZATION OF DOSAGE REGIMENS: PHARMACOKINETIC DATA
TABULATED PHARMACOKINETIC
PARAMETERS
Each of the eight parameters presented in Table AII–1
has been discussed in detail in Chapter 2. The following
discussion focuses on the format in which the values
are presented as well as on factors (physiological
or pathological) that influence the parameters.
Bioavailability. The extent of oral bioavailability is
expressed as a percentage of the administered dose.
This value represents the percentage of the administered
dose that is available to the systemic circulation—
the fraction of the oral dose that reaches the arterial
blood in an active or prodrug form, expressed as a percentage
(0-100). Fractional availability (F), which
appears elsewhere in this appendix, denotes the same
parameter; this value varies from 0-1. Measures of both
the extent and rate (see T max
) of availability are presented
in the table. The extent of availability is needed
for the design of an oral dosage regimen to achieve a
specific target blood concentration. Values for multiple
routes of administration are provided, when appropriate
and available. In most cases, the tabulated value represents
an absolute oral bioavailability that has been
determined from a comparison of area under the plasma
drug concentration–time curve (AUC) between the oral
dose and an intravenous reference dose. For those drugs
where intravenous administration is not feasible, an
approximate estimate of oral bioavailability based on
secondary information (e.g., urinary excretion of
unchanged drug, especially when the nonrenal route of
elimination is minimal) is presented, or the column is
left blank (denoted by a long dash [—]). A dash also
will appear when a drug is given by parenteral administration
only.
A low bioavailability may result from a poorly
formulated dosage form that fails to disintegrate or dissolve
in the gastrointestinal fluid, degradative loss of
drug in the gastrointestinal fluid, poor mucosal permeability,
first-pass metabolism during transit through the
intestinal epithelium, active efflux transport of drug
back into the lumen, or first-pass hepatic metabolism
or biliary excretion (see Chapter 2). In the case of drugs
with extensive first-pass metabolism, hepatic disease
may increase oral availability because hepatic metabolic
capacity decreases and/or because vascular shunts
develop around the liver.
Urinary Excretion of Unchanged Drug. The second parameter
in Table AII–1 is the amount of drug eventually
excreted unchanged in the urine, expressed as a