[Genetic polymorphism and metabolism of tricyclic antidepressants]

Abstract

Steady state plasma concentration of orally administered tricyclic antidepressants varies markedly between individuals. This is partly explained by a recent notion: pharmacogenetic, as interindividual differences in the capacity of the liver to extract and metabolize them. Different studies indicate that N-dimethylation and 10-hydroxylation of tricyclic antidepressants are regulated by different enzymatic mechanisms. The 10-hydroxylation is under the same genetic control as hydroxylation of debrisoquin or demethylation of dextromethorphan. They are metabolized by the same cytochrome P450 isoenzyme. Monogenic control has been described for debrisoquin 4-hydroxylation and for dextromethorphan O-demethylation. The ratio between debrisoquin and 4-hydroxydebrisoquin or dextromethorphan and dextromethorphan O demethylated, in urine, after a single oral dose is bimodally distributed. A correlation between most of tricyclic antidepressants plasma concentration and metabolic ratio of debrisoquin or dextromethorphan has been demonstrated. Currently, the posology for a drug is established without taking into account slow-hydroxylator phenotype which is more exposed to adverse reactions.