The metabolic fate of amitriptyline, nortriptyline and amitriptylinoxide in man.
Amitriptyline (AT), the most widely used tricyclic antidepressant, undergoes oxidative metabolism in the side chain with production of the secondary amine nortriptyline (NT), a primary amine, and the N-oxide amitriptylinoxide (AT-NO); in addition, direct conjugation leads to a quaternary ammonium-linked glucuronide. Hydroxylation of AT or NT at the ethylene bridge of the central seven-membered ring results in four isomeric alcohols and occurs with high stereo- and enantioselectivity, the (-)-(E)-10-hydroxy compounds usually being the major products. The disposition of the alcohols is also partially enantioselective, for instance with regard to glucuronidation and reversible oxidation to ketones. Introduction of a second hydroxy group results in isomeric glycols. Oxidative attack at an aromatic ring is a minor pathway leading to dihydrodiols and phenols. Numerous metabolites originate by combinations of reactions in the ring system and the side chain. AT-NO is by about one-third excreted in unchanged form or as 10-hydroxy derivative; the major part is reduced to AT and metabolized further. The review covers current knowledge on the enzymes participating in the individual pathways. Their quantitative importance is inferred from kinetic studies in volunteers and patients and from experiments in vitro. Clinical consequences of biochemical findings mainly derive from the impact of the polymorphic CYP2D6 mediating (-)-(E)-10-hydroxylation and from its potential inhibition by other psychoactive drugs.
Breyer-Pfaff
Ursula
U
Department of Pharmacology and Toxicology, University of Tübingen, Tübingen, Germany.
D000639:Amitriptyline / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D009661:Nortriptyline / Q000737:chemistry / Q000378:metabolism*
D000639:Amitriptyline; D009661:Nortriptyline; C006566:amitriptyline N-oxide