Clinical Pharmacology and Therapeutics

28 DRUG METABOLISM
TESTS FOR INDUCTION OF DRUG-
METABOLIZING ENZYMES
enzymes and inhibits phenytoin, warfarin and sulphonylurea
(e.g. glyburide) metabolism.
The activity of hepatic drug-metabolizing enzymes can be
assessed by measuring the clearance or metabolite ratios of
probe drug substrates, e.g. midazolam for CYP3A4, dextromethorphan
for CYP2D6, but this is seldom if ever indicated
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 elimination
and also in several other biological processes, including
adaptation to extra-uterine life. Neonates fail to form glucuronide
conjugates because of immaturity of hepatic uridyl
glucuronyl transferases with clinically important consequences,
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 warfarin and theophylline (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 incomplete.
For example, warfarin and phenytoin compete with
one another for metabolism, and co-administration results in
elevation of plasma steady-state concentrations of both drugs.
Metronidazole is a non-competitive inhibitor of microsomal
Inhibitor
Rapid
Direct inhibition
of CYP450
isoenzyme(s)
Figure 5.3: Enzyme inhibition.
↓ Metabolism
(↑ t ½ )
of target drug
↑ Plasma concentration
of target drug
↑ Effect
↑ Toxicity
of target drug
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 distribution
to other tissues and drug elimination by other routes.
If a drug is subject to a high hepatic clearance (i.e. it is rapidly
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 example,
when salbutamol is given to asthmatic subjects, the ratio
of unchanged drug to metabolite in the urine is 2:1 after intravenous
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 administration,
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 relationship,
although linear, does not pass through the origin and
there is a threshold dose below which measurable concentrations
of propranolol are 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, morphine,
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 usually
exhibit pronounced inter-individual variability in drug disposition.
This results in highly variable responses to therapy,