Clinical Pharmacology and Therapeutics

METABOLISM OF DRUGS BY INTESTINAL ORGANISMS 29
First-pass
metabolism
Orally
administered
drug
Intestinal
mucosal
metabolism
Portal
vein
Hepatic
metabolism
Systemic
circulation
Parenterally
administered
drug
Figure 5.4: Presystemic (‘first-pass’) metabolism.
1000
i.v.
Oral
5. Non-linear first-pass kinetics are common (e.g. aspirin,
hydralazine, propranolol): increasing the dose
disproportionately increases bioavailability.
6. Liver disease increases the bioavailability of some drugs
with extensive first-pass extraction (e.g. diltiazem,
ciclosporin, morphine).
Area (ng/ml h)
500
0
0
T
40 80 120 160
Dose (mg)
Figure 5.5: Area under blood concentration–time curve after oral
() and intravenous () administration of propranolol to humans
in various doses. T is the apparent threshold for propranolol
following oral administration. (Redrawn from Shand DG, Rangno
RE. Pharmacology 1972; 7: 159, with permission of
S Karger AG, Basle.)
and is one of the major difficulties in their clinical use.
Variability in first-pass metabolism results from:
1. Genetic variations – for example, the bioavailability of
hydralazine is about double in slow compared to fast
acetylators. Presystemic hydroxylation of metoprolol and
encainide also depends on genetic polymorphisms
(CYP2D6, Chapter 14).
2. Induction or inhibition of drug-metabolizing enzymes.
3. Food increases liver blood flow and can increase the
bioavailability of drugs, such as propranolol, metoprolol
and hydralazine, by increasing hepatic blood flow and
exceeding the threshold for complete hepatic extraction.
4. Drugs that increase liver blood flow have similar effects to
food – for example, hydralazine increases propranolol
bioavailability by approximately one-third, whereas drugs
that reduce liver blood flow (e.g. -adrenoceptor
antagonists) reduce it.
METABOLISM OF DRUGS BY INTESTINAL
ORGANISMS
This is important for drugs undergoing significant enterohepatic
circulation. For example, in the case of estradiol, which is
excreted in bile as a glucuronide conjugate, bacteria-derived
enzymes cleave the glucuronide so that free drug is available
for reabsorption in the terminal ileum. A small proportion of
the dose (approximately 7%) is excreted in the faeces under
normal circumstances; this increases if gastro-intestinal disease
or concurrent antibiotic therapy alter the intestinal flora.
Key points
• Drug metabolism involves two phases: phase I often
followed sequentially by phase II.
• Phase I metabolism introduces a reactive group into a
molecule, usually by oxidation, by a microsomal system
present in the liver.
• The CYP450 enzymes are a superfamily of
haemoproteins. They have distinct isoenzyme forms
and are critical for phase I reactions.
• Products of phase I metabolism may be
pharmacologically active, as well as being chemically
reactive, and can be hepatotoxic.
• Phase II reactions involve conjugation (e.g. acetylation,
glucuronidation, sulphation, methylation).
• Products of phase II metabolism are polar and can be
efficiently excreted by the kidneys. Unlike the products
of phase I metabolism, they are nearly always
pharmacologically inactive.
• The CYP450 enzymes involved in phase I metabolism can
be induced by several drugs and nutraceuticals (e.g.
glucocorticosteroids, rifampicin, carbamazepine, St John’s
wort) or inhibited by drugs (e.g. cimetidine, azoles, HIV
protease inhibitors, quinolones, metronidazole) and
dietary constituents (e.g. grapefruit/grapefruit juice).
• Induction or inhibition of the CYP450 system are
important causes of drug–drug interactions (see
Chapter 13).