A Textbook of Clinical Pharmacology and Therapeutics

●Introduction 17

●Bioavailability, bioequivalence and generic vs.

proprietary prescribing 17

●Prodrugs 18

●Routes of administration 19

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 mem-
branes. These are permeable to lipid-soluble drugs, whilst pre-
senting 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 experi-
mentally (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 intra-
venously (i.v.).

BioavailabilityAUCoral/AUCi.v.100%

Many factors in the manufacture of the drug formulation influ-
ence its disintegration, dispersion and dissolution in the gastro-
intestinal tract. Pharmaceutical factors are therefore important
in determining bioavailability. It is important to distinguish

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 epi-

demic of phenytoin intoxication in Australia in 1968–69.

Affected patients were found to be taking one brand of pheny-

toin: the excipient had been changed from calcium sulphate to

lactose, increasing phenytoinbioavailability and thereby pre-

cipitating toxicity. An apparently minor change in the manufac-

turing process of digoxin in the UK resulted in reduced potency

due to poor bioavailability. Restoring the original manufactur-

ing 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

Systemic

circulation

Oral

administration

Inactivation

in liver

Inactivation

in gut lumen

Inactivation

in stomach

Inactivation

in gut wall

Portal blood

Incomplete

absorption

Figure 4.1:Drug bioavailability following oral administration may

be incomplete for several reasons.