A Textbook of Clinical Pharmacology and Therapeutics

28 DRUG METABOLISM

TESTS FOR INDUCTION OF DRUG-

METABOLIZING ENZYMES

The activity of hepatic drug-metabolizing enzymes can be
assessed by measuring the clearance or metabolite ratios of
probe drug substrates, e.g. midazolamfor CYP3A4, dex-
tromethorphanfor CYP2D6, but this is seldom if ever indi-
cated clinically. The^14 C-erythromycin breath test or the urinary
molar ratio of 6-beta-hydroxycortisol/cortisol have also been
used to assess CYP3A4 activity. It is unlikely that a single probe
drug study will be definitive, since the mixed function oxidase
(CYP450) system is so complex that at any one time the activity
of some enzymes may be increased and that of others reduced.
Induction of drug metabolism represents variable expression
of a constant genetic constitution. It is important in drug elim-
ination and also in several other biological processes, including
adaptation to extra-uterine life. Neonates fail to form glu-
curonide conjugates because of immaturity of hepatic uridyl
glucuronyl transferases with clinically important conse-
quences, e.g. grey baby syndrome with chloramphenicol
(Chapter 10).

ENZYME INHIBITION

Allopurinol, methotrexate, angiotensin converting enzyme
inhibitors, non-steroidal anti-inflammatory drugs and many
others, exert their therapeutic effects by enzyme inhibition
(Figure 5.3). Quite apart from such direct actions, inhibition of
drug-metabolizing enzymes by a concurrently administered
drug (Table 5.1) can lead to drug accumulation and toxicity.
For example, cimetidine, an antagonist at the histamine
H 2 -receptor, also inhibits drug metabolism via the CYP450
system and potentiates the actions of unrelated CYP450
metabolized drugs, such as warfarinandtheophylline(see
Chapters 13, 30 and 33). Other potent CYP3A4 inhibitors
include the azoles (e.g. fluconazole,voriconazole) and HIV
protease inhibitors (e.g. ritonavir).
The specificity of enzyme inhibition is sometimes incom-
plete. For example, warfarinandphenytoincompete with
one another for metabolism, and co-administration results in
elevation of plasma steady-state concentrations of both drugs.
Metronidazoleis a non-competitive inhibitor of microsomal

enzymes and inhibits phenytoin,warfarinandsulphonylurea

(e.g.glyburide) metabolism.

PRESYSTEMIC METABOLISM (‘FIRST-PASS’

EFFECT)

The metabolism of some drugs is markedly dependent on the

route of administration. Following oral administration, drugs

gain access to the systemic circulation via the portal vein, so the

entire absorbed dose is exposed first to the intestinal mucosa

and then to the liver, before gaining access to the rest of the

body. A considerably smaller fraction of the absorbed dose goes

through gut and liver in subsequent passes because of distribu-

tion to other tissues and drug elimination by other routes.

If a drug is subject to a high hepatic clearance (i.e. it is rap-

idly metabolized by the liver), a substantial fraction will be

extracted from the portal blood and metabolized before it

reaches the systemic circulation. This, in combination with

intestinal mucosal metabolism, is known as presystemic or

‘first-pass’ metabolism (Figure 5.4).

The route of administration and presystemic metabolism

markedly influence the pattern of drug metabolism. For exam-

ple, when salbutamolis given to asthmatic subjects, the ratio

of unchanged drug to metabolite in the urine is 2:1 after intra-

venous administration, but 1:2 after an oral dose. Propranolol

undergoes substantial hepatic presystemic metabolism, and

small doses given orally are completely metabolized before

they reach the systematic circulation. After intravenous admin-

istration, the area under the plasma concentration–time curve

is proportional to the dose administered and passes through

the origin (Figure 5.5). After oral administration the relation-

ship, although linear, does not pass through the origin and

there is a threshold dose below which measurable concentra-

tions of propranololare not detectable in systemic venous

plasma. The usual dose of drugs with substantial presystemic

metabolism differs very markedly if the drug is given by

the oral or by the systemic route (one must never estimate or

guess the i.v. dose of a drug from its usual oral dose for this

reason!) In patients with portocaval anastomoses bypassing

the liver, hepatic presystemic metabolism is bypassed, so

very small drug doses are needed compared to the usual

oral dose.

Presystemic metabolism is not limited to the liver, since the

gastro-intestinal mucosa contains many drug-metabolizing

enzymes (e.g. CYP3A4, dopa-decarboxylase, catechol-

O-methyl transferase (COMT)) which can metabolize drugs, e.g.

ciclosporin, felodipine,levodopa, salbutamol, before they

enter hepatic portal blood. Pronounced first-pass metabolism by

either the gastro-intestinal mucosa (e.g. felodipine,salbutamol,

levodopa) or liver (e.g. felodipine,glyceryl trinitrate,mor-

phine,naloxone,verapamil) necessitates high oral doses by

comparison with the intravenous route. Alternative routes of

drug delivery (e.g. buccal, rectal, sublingual, transdermal) partly

or completely bypass presystemic elimination (Chapter 4).

Drugs undergoing extensive presystemic metabolism usu-

ally exhibit pronounced inter-individual variability in drug dis-

position. This results in highly variable responses to therapy,

Inhibitor Direct inhibition

of CYP450

isoenzyme(s)

↓ Metabolism

(↑t½)

of target drug

Rapid

↑ Plasma concentration

of target drug

↑ Effect

↑ Toxicity

of target drug

Figure 5.3:Enzyme inhibition.