Genetic polymorphism in drug oxidation.

Of the two clearly established drug oxidation polymorphisms, only the one referred to as debrisoquine polymorphism affects many drugs. The only known polymorphic substrates of mephenytoin hydroxylase are mephenytoin and mephobarbital. Relatively recently discovered drug substrates of debrisoquine hydroxylase are propafenone, diltiazem, and codeine. The list of substrates contains 28 items. The fate of slightly less than half of these is clinically affected in poor metabolizers, and several of the latter drugs are no longer marketed. There are many reasons why a failure of metabolism may not alter the fate of a drug sufficiently to affect its clinical use. Of interest and clinical importance is the inhibition of debrisoquine hydroxylase by inhibitors such as quinidine and by some neuroleptics; also the simultaneous use of two substrates has led to serious toxicity by mutual metabolic inhibition. The study of these oxidation polymorphisms has been instructive not only for formal pharmacogenetics but also for the understanding of problems of therapy in patients without genetic defects.