A Textbook of Clinical Pharmacology and Therapeutics

METABOLISM OFDRUGS BYINTESTINALORGANISMS 29

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
   hydralazineis about double in slow compared to fast
   acetylators. Presystemic hydroxylation of metoprololand
   encainidealso 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
   andhydralazine, 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, hydralazineincreases propranolol
   bioavailability by approximately one-third, whereas drugs
   that reduce liver blood flow (e.g. -adrenoceptor
   antagonists) reduce it.

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).

METABOLISM OF DRUGS BY INTESTINAL

ORGANISMS

This is important for drugs undergoing significant enterohep-

atic 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 dis-

ease or concurrent antibiotic therapy alter the intestinal flora.

Orally

administered

drug

Intestinal

mucosal

metabolism

Portal

vein Hepatic

metabolism

Systemic

circulation

First-pass

metabolism

Parenterally

administered

drug Figure 5.4:Presystemic (‘first-pass’) metabolism.

i.v.

Oral

0

0

500

1000

40 80 120 160

Area (ng/ml h)

T 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.Pharmacology1972; 7 : 159, with permission of
S Karger AG, Basle.)

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).