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To the Editor:
Amitriptyline belongs to the class of tricyclic antidepressants (TCAs), which have been a cornerstone of antidepressive therapy for more than 4 decades. Despite being replaced by newer drugs in the United States, TCAs, and amitriptyline in particular, are still widely used in Europe and many parts of the world, where prescriptions for TCAs far outnumber those for newer, more expensive drugs.
Recently, we reported significant correlations between sequence variations in the genes that encode the metabolizing enzymes cytochrome P450 2D6 (CYP2D6) and 2C19 (CYP2C19), serum amitriptyline/nortriptyline concentrations, and adverse drug reactions in a population of 50 depressed inpatients (1,2 ).
However, genetic variations in drug-metabolizing enzymes do not sufficiently explain the wide interindividual variations commonly observed in drug response and clinical outcome. Obviously, other genetic and environmental factors must be considered as well. The influence of sequence variations in the gene ATP-binding cassette, subfamily B (MDR/ TAP), member 1 (ABCBl) on the disposition and efficacy of P-glycoprotein (P-gp) substrates (e.g., TCAs) is currently being discussed (3).
As part of the blood-brain barrier, P-gp actively exports significant amounts of antidepressant from the brain. Recent studies showed that penetration of amitriptyline and its metabolites (including nortriptyline) into the brain is enhanced in mice lacking P-gp (4, 5). Therefore, dysfunctional sequence variants of the ABCB1 gene might lead to diminished P-gp activity and higher bioavailability of P-gp substrates in the central nervous system. The nonsynonymous G2677T/A sequence variation (Ala893Ser/Thr) in ABCBl can be used to differentiate between the 2 most common haplotypes found in Caucasians. We...