Polymorphic drug oxidation - Relevance to the treatment of psychiatric disorders

Plasma drug concentrations and response to drugs vary considerably between patients during treatment with psychotropic drugs, Many antidepressant and antipsychotic drugs are metabolisod by the polymorphic debrisoquine/sparteine hydroxylase, i,e, cytochrome P450 (CYP) 2D6, which is absent in 7% of Caucasians [these individuals are termed 'poor metabolisers' (PM)]. Such PM might develop adverse drug reactions while receiving usual dosages of drugs due to high plasma drug concentrations, In contrast, ultrarapid metabolisers with multiple CYP2D6 genes might require high doses of such drugs for optimal therapy, The mean CYP2D6 activity is lower in Oriental than in Caucasian populations, because of a frequent mutation in exon 1 of CYP2D6, causing decreased enzyme activity, This may partly explain the use of lower doses of antidepressants and antipsychotics in Oriental than in Caucasian individuals, In contrast to other antipsychotics, clozapine is not metabolised by CYP2D6 to a major extent, but by CYP1A2. This latter isozyme is induced by tobacco smoking. The hydroxylation of S-mephenytoin is catalysed by the polymorphic CYP2C19 isozyme. About 3% of Caucasians, but as many as 12 to 20% of Oriental persons, are PM of S-mephenytoin and of omeprazole, another CYP2C19 substrate. Among psychotropic drugs, tertiary amine antidepressants (amitriptyline, citalopram, clomipramine and imipramine) are N-demethylated by CYP2C19. Both diazepam and its demethyl metabolite are partly metabolised by this polymorphic enzyme. The high incidence of PM (and of heterozygous extensive metabolisers) of S-mephenytoin in Asia might be the reason for the reported higher sensitivity of Orientals to diazepam compared with Caucasians. Various probe drugs may be used for phenotyping of CYP2D6 (debrisoquine, dextromethorphan and sparteine) and CYP2C19 (mephenytoin and omeprazole). Allele-specific polymerase chain reaction (PCR)-based methods are now available for genotyping using leucocyte DNA. A major advantage of genotyping over phenotyping is that the former may be performed using blood samples from patients irrespective of treatment with psychotropic drugs.