Principles and Practice of Pharmaceutical Medicine

Elementary aspects of oral
bioavailability

The oral bioavailability (F) of a drug is dependent
on (a) the absorption of the drug from the gastro-
intestinal (GI) tract and (b) the capability of the
liver to clear the drug during its first pass through
the portal venous system. Oral bioavailability may
be described as the fraction of the total oral dose for
which systemic exposure is achieved. It is a mea-
surement of theextentof exposure and contrasts
with the rates of absorption or elimination
discussed above.
Clinically,Fis found by comparing the systemic
exposures that result after intravenous and
(usually) oral doses of the same drug. Note that
this comparison need not be for doses of the same
size (an important consideration when assessing
the tolerability aspects of a proposed normal volun-
teer study). It is, in fact, preferable to achieve
concentrations in the same range from the two
doses. Typically, Cmax for a standard dose is
going to be higher after bolus intravenous dosing
(IV) than after oral administration (PO), and
adverse effects of new agents are likely to be con-
centration dependent. The relevant equation is:

Fð%Þ¼½ðAUCPODoseIVÞ=

ðAUCIVDosePOފ 100 %

whereAUCis the area under the time–plasma con-
centration curve after each of the respective admin-
istrations (the dose terms cancel when equally sized
doses are administered by both routes of adminis-
tration). A residual of less than 15% (sometimes
10%) of the totalAUCis a commonly used standard
for timing the last plasma sample. These studies are
usually conducted under standard conditions and
using crossover protocols, although, occasionally,
a double-label study may be used to measureF
instantaneously. Comparison of generic with inno-
vator’s formulations, and slow-release with rapidly
absorbed formulations, may be done using equa-
tions of the same form. Similarly, subcutaneous and
intravenous injections can be compared. With very
rare exceptions, the intravenous administration of a
dose is assumed to be 100% bioavailable. For

example, very short-acting drugs, for example

some arachidonate derivatives, remifentanil, esmo-

lol and adenosine, may be metabolized during their

first return circulation after intravenous administra-

tion and still not achieve 100% ‘bioavailability’.

Also, the concept is not applicable to topically

acting drugs. However, assessing the bioavailability

of these drugs byany otherroute of administration is

usually pointless, unless there is some highly

specialized issue, for example absorption after

intrathecal administration or potential for drug

abuse.

Fluctuation of plasma drug concentration is an

important aspect of the bioavailability of slow-

release formulations, which almost always have

lowerCmaxvalues for a standard dose size than,

albeit similar AUC to, a more rapidly absorbed

tablet. Assuming that the assay can handle the

inevitably lower plasma concentrations, a useful

measure of fluctuation, after the initial absorption

phase of the curve and during the next four half-

lives of elimination, is:

ðCmax
CminÞ=Cavg

whereCavgis the average concentration during the

specified time period; whether to use the arithmetic

or geometric average is a controversy, with

respected protagonists on both sides.

Prediction of oral bioavailability

Oral bioavailability can be predicted using the

following equation:

F¼Fað 1 
Cl=QÞ

where Fa represents the fraction of drug absorbed

through the intestinal lining, Cl is the hepatic

clearance (predicted fromin vitrostudies, see ear-

lier section) and Qis the hepatic blood flow

in humans (see, for example Raneet al., 1977).

Octanol/water partitioning has traditionally been

used to predict the fraction absorbed through the

intestinal lining. Recently, Caco-2 cell permeabil-

ity studies have replaced the use of octanol/buffer

partitioning studies. Yee (1997) established a

8.1 THE IN VITRO/IN VIVO PREDICTION 85