The clinical significance of two separate genetic polymorphisms which alter
drug metabolism, acetylation and oxidation is discussed, and methods of phenotyping for both acetylator and polymorphic oxidation status are reviewed. Particular reference is made to the
dapsone method, which provides a simple means of distinguishing fast and slow - and possibly intermediate - acetylators, and to the
sparteine method which allows a clear separation of oxidation phenotypes. Although acetylation polymorphism has been known for some time, definite indications for phenotyping are few. It is doubtful whether acetylator phenotype makes a significant difference to the outcome in most
isoniazid treatment regimens, and
peripheral neuropathy from
isoniazid in slow acetylators is easily overcome by
pyridoxine administration. However, in comparison with rapid acetylators, slow acetylators receiving
isoniazid have an increased susceptibility to
phenytoin toxicity, and perhaps also to
carbamazepine toxicity. It is also possible that rapid acetylators receiving
isoniazid attain higher serum
fluoride concentrations from
enflurane and similar anaesthetics than do similarly treated slow acetylators. Thus, when drug interactions of these types are suspected, phenotyping for acetylator status may be advisable. If routine monitoring of serum
procainamide and
N-acetylprocainamide concentrations is practised, phenotyping of subjects prior to
therapy with these agents should not be necessary. Although acetylator phenotype influences serum concentrations of
hydralazine, when this
drug is given in combination with other drugs acetylator phenotype has not been shown to influence the therapeutic response. Slow acetylator phenotype along with female gender and the presence of
HLA-DR antigens appear to be risk factors in the development of
hydralazine-induced
systemic lupus erythematosus (SLE). Determination of acetylator phenotype may therefore help determine susceptibility to this adverse reaction. In the case of
sulphasalazine, adult slow acetylators require a lower daily dose of the
drug than fast acetylators in order to maintain
ulcerative colitis in remission without significant side effects. It is therefore advisable to determine acetylator phenotype prior to
sulphasalazine therapy. Work on the association of acetylation polymorphism with various disease states is also reviewed. It is possible that a higher incidence of
bladder cancer is associated with slow acetylation phenotype - especially in individuals exposed to high levels of arylamines. The question as to whether idiopathic SLE is more common in slow acetylators remains unresolved. There appears to be no difference between fa