A Textbook of Clinical Pharmacology and Therapeutics

● Introduction 17
● Bioavailability, bioequivalence and generic vs.
proprietary prescribing 17
CHAPTER 4
DRUG ABSORPTION AND ROUTES
OF ADMINISTRATION
INTRODUCTION
Drug absorption, and hence the routes by which a particular
drug may usefully be administered, is determined by the rate
and extent of penetration of biological phospholipid membranes.
These are permeable to lipid-soluble drugs, whilst presenting
a barrier to more water-soluble drugs. The most
convenient route of drug administration is usually by mouth,
and absorption processes in the gastro-intestinal tract are
among the best understood.
BIOAVAILABILITY, BIOEQUIVALENCE AND
GENERIC VS. PROPRIETARY PRESCRIBING
Drugs must enter the circulation if they are to exert a systemic
effect. Unless administered intravenously, most drugs are
absorbed incompletely (Figure 4.1). There are three reasons
for this:
1. the drug is inactivated within the gut lumen by gastric
acid, digestive enzymes or bacteria;
2. absorption is incomplete; and
3. presystemic (‘first-pass’) metabolism occurs in the gut
wall and liver.
Together, these processes explain why the bioavailability of
an orally administered drug is typically less than 100%.
Bioavailability of a drug formulation can be measured experimentally
(Figure 4.2) by measuring concentration vs. time
curves following administration of the preparation via its
intended route (e.g. orally) and of the same dose given intravenously
(i.v.).
Bioavailability � AUCoral/AUCi.v. � 100%
Many factors in the manufacture of the drug formulation influence
its disintegration, dispersion and dissolution in the gastrointestinal
tract. Pharmaceutical factors are therefore important
in determining bioavailability. It is important to distinguish
● Prodrugs 18
● Routes of administration 19
Inactivation
in liver
Systemic
circulation
Portal blood
Inactivation
in gut wall
Oral
administration
Inactivation
in stomach
Inactivation
in gut lumen
Incomplete
absorption
Figure 4.1: Drug bioavailability following oral administration may
be incomplete for several reasons.
statistically significant from clinically important differences in
this regard. The former are common, whereas the latter are not.
However, differences in bioavailability did account for an epidemic
of phenytoin intoxication in Australia in 1968–69.
Affected patients were found to be taking one brand of phenytoin:
the excipient had been changed from calcium sulphate to
lactose, increasing phenytoin bioavailability and thereby precipitating
toxicity. An apparently minor change in the manufacturing
process of digoxin in the UK resulted in reduced potency
due to poor bioavailability. Restoring the original manufacturing
conditions restored potency but led to some confusion, with
both toxicity and underdosing.
These examples raise the question of whether prescribing
should be by generic name or by proprietary (brand) name.
When a new preparation is marketed, it has a proprietary name