Page 61 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 3 Pharmacokinetics & Pharmacodynamics: Rational Dosing & the Time Course of Drug Action 47

half-life. A convenient index of accumulation is the accumula-
Concentration of drug in blood TC
tion factor:

(7)
C
A
B
Time
For a drug given once every half-life, the accumulation factor
is 1/0.5, or 2. The accumulation factor predicts the ratio of the A: Drug rapidly and completely available
steady-state concentration to that seen at the same time following B: Only half of availability of A but rate equal to A
the first dose. Thus, the peak concentrations after intermittent C: Drug completely available but rate only half of A
doses at steady state will be equal to the peak concentration after
the first dose multiplied by the accumulation factor. FIGURE 3–4 Blood concentration-time curves illustrating how
changes in the rate of absorption and extent of bioavailability can
Bioavailability influence both the duration of action and the effectiveness of the
same total dose of a drug administered in three different formula-
Bioavailability is defined as the fraction of unchanged drug reach- tions. The dashed line indicates the target concentration (TC) of the
ing the systemic circulation following administration by any route drug in the blood.
(Table 3–3). The area under the blood concentration-time curve
(AUC) is proportional to the dose and the extent of bioavailability
for a drug if its elimination is first-order (Figure 3–4). For an intra- This is mainly due to lack of absorption from the gut. Other drugs are
venous dose, bioavailability is assumed to be equal to unity. For a either too hydrophilic (eg, atenolol) or too lipophilic (eg, acyclovir)
drug administered orally, bioavailability may be less than 100% for to be absorbed easily, and their low bioavailability is also due to
two main reasons—incomplete extent of absorption across the gut incomplete absorption. If too hydrophilic, the drug cannot cross
wall and first-pass elimination by the liver (see below). the lipid cell membrane; if too lipophilic, the drug is not soluble
enough to cross the water layer adjacent to the cell. Drugs may
A. Extent of Absorption not be absorbed because of a reverse transporter associated with
After oral administration, a drug may be incompletely absorbed, P-glycoprotein. This process actively pumps drug out of gut wall
eg, only 70% of a dose of digoxin reaches the systemic circulation. cells back into the gut lumen. Inhibition of P-glycoprotein and
gut wall metabolism, eg, by grapefruit juice, may be associated
with substantially increased drug absorption.
TABLE 3–3 Routes of administration, bioavailability,
and general characteristics. B. First-Pass Elimination
Following absorption across the gut wall, the portal blood delivers
Route Biovailability (%) Characteristics
the drug to the liver prior to entry into the systemic circulation.
Intravenous (IV) 100 (by definition) Most rapid onset A drug can be metabolized in the gut wall (eg, by the CYP3A4
Intramuscular (IM) 75 to ≤100 Large volumes often enzyme system) or even in the portal blood, but most commonly
feasible; may be it is the liver that is responsible for metabolism before the drug
painful reaches the systemic circulation. In addition, the liver can excrete
Subcutaneous (SC) 75 to ≤100 Smaller volumes than the drug into the bile. Any of these sites can contribute to this
IM; may be painful reduction in bioavailability, and the overall process is known as
Oral (PO) 5 to <100 Most convenient; first-pass elimination. The effect of first-pass hepatic elimination
first-pass effect may on bioavailability is expressed as the extraction ratio (ER):
be important
Rectal (PR) 30 to <100 Less first-pass effect
than oral (8a)

Inhalation 5 to <100 Often very rapid
onset where Q is hepatic blood flow, normally about 90 L/h in a person
Transdermal 80 to ≤100 Usually very slow weighing 70 kg.
absorption; used The systemic bioavailability of the drug (F) can be predicted
for lack of first-pass from the extent of absorption (f) and the extraction ratio (ER):
effect; prolonged
duration of action
(8b)