A Textbook of Clinical Pharmacology and Therapeutics

for Ry1R or undergo muscle biopsy to assess their predisposi-
tion to this condition. Muscle from affected individuals is
abnormally sensitive to caffeinein vitro, responding with a
strong contraction to low concentrations. (Pharmacological
doses of caffeinerelease calcium from intracellular stores
and cause contraction even in normal muscle at sufficiently
high concentration.) Affected muscle responds similarly to
halothaneorsuxamethonium.

ACUTE PORPHYRIAS

This group of diseases includes acute intermittent porphyria,
variegate porphyria and hereditary coproporphyria. In each
of these varieties, acute illness is precipitated by drugs
because of inherited enzyme deficiencies in the pathway of
haem biosynthesis (Figure 14.5). Drugs do not precipitate
acute attacks in porphyria cutanea tarda, a non-acute por-
phyria, although this condition is aggravated by alcohol,
oestrogens, iron and polychlorinated aromatic compounds.

Drug-induced exacerbations of acute porphyria (neuro-

logical, psychiatric, cardiovascular and gastro-intestinal dis-

turbances that are occasionally fatal) are accompanied by

increased urinary excretion of 5-aminolevulinic acid (ALA)

and porphobilinogen. An extraordinarily wide array of drugs

can cause such exacerbations. Most of the drugs that have

been incriminated are enzyme inducers that raise hepatic ALA

synthetase levels. These drugs include phenytoin, sulphonyl-

ureas, ethanol,griseofulvin, sulphonamides, sex hormones,

methyldopa, imipramine, theophylline, rifampicin and

pyrazinamide. Often a single dose of one drug of this type can

precipitate an acute episode, but in some patients repeated

doses are necessary to provoke a reaction.

Specialist advice is essential. A very useful list of drugs that

are unsafe to use in patients with porphyrias is included in the

British National Formulary.

GILBERT’S DISEASE

This is a benign chronic form of primarily unconjugated hyper-

bilirubinaemia caused by an inherited reduced activity/lack of

the hepatic conjugating enzyme uridine phosphoglucuronyl

transferase (UGT1A1). Oestrogens impair bilirubin uptake and

aggravate jaundice in patients with this condition, as does pro-

tracted fasting. The active metabolite of irinotecanis glu-

curonidated by UGT1A1, so irinotecantoxicity is increased in

Gilbert’s disease.

84 PHARMACOGENETICS

Figure 14.5:Porphyrin metabolism, showing sites of enzyme
deficiency.

Glycine succinyl CoA

-aminolevulinic acid (ALA)

Porphobilinogen (PBG)

Hydroxymethylbilane

Uroporphyrinogen (UPG) III

Coproporphyrinogen (CPG) III

Uroporphyrin

Coproporphyrin

UPG decarboxylase

UPG III synthetase

PBG

deaminase

CPG

oxidase

PPG

oxidase

Ferrochelatase

Protoporphyrinogen (PPG)

Protoporphyrin IX

Haem

ALA synthetase

CO 2

Deficient in

acute intermittent

porphyria

Deficient in

hereditary

coproporphyria

Deficient in

variegate

porphyria

Case history

A 26-year-old Caucasian woman has a three-month history

of intermittent bloody diarrhoea and is diagnosed with

ulcerative colitis. She is initially started on oral prednisolone

30 mg/day and sulfasalazine 1 g four times a day with little

improvement in her colitic symptoms. Her gastroenterolo-

gist, despite attempting to control her disease with increas-

ing doses of her initial therapy, reverts to starting low-dose

azathioprine at 25 mg three times a day and stopping her

sulfasalazine. Two weeks later, on review, her symptoms of

colitis have improved, but she has ulcers on her oropharynx

with a sore mouth. Her Hb is 9.8 g/dL and absolute neu-

trophil count is 250/mm^3 and platelet count 85 000.

Question

What is the most likely cause of this clinical situation?

Answer

The patient has haematopoietic toxicity due to azathioprine

(a prodrug of 6-MP). 6-MP is inactivated by the enzyme

thiopurine methyltransferase (TPMT). In Caucasians 0.3%

(one in 300) of patients are genetically deficient in this

enzyme because of polymorphisms in the gene (*3/*4 is

most common) and 11% of Caucasians who have a het-

erozygous genotype have low levels of the enzyme. Patients

with absent or low TPMT expression are at a higher risk of

bone marrow suppression. In this patient, the azathioprine

should be stopped and her TPMT genotype defined. Once

her bone marrow has recovered (with or without

haematopoietic growth factors), she could be restarted on

very low doses (e.g 6.25–12 mg azathioprine daily).