Amitriptyline metabolism: association with debrisoquin hydroxylation in nonsmokers.
Eleven healthy nonsmokers with wide variation in the ability to hydroxylate debrisoquin (D) were given single oral doses of amitriptyline and nortriptyline on different occasions. The urinary D/4-hydroxy-D ratio correlated significantly (P less than 0.01) with all three parameters of amitriptyline disposition measured (total plasma clearance, clearance by demethylation, and clearance by pathways other than demethylation), with rs = -0.89, -0.78, and -0.83, respectively. In contrast, we failed to demonstrate such correlations in a previous sample of smokers. Our data suggest that there may be a common regulation of the hydroxylation of D and the oxidative metabolism of amitriptyline in nonsmokers. It is hypothesized that an additional demethylase/hydroxylase is induced in smokers that is not involved in D hydroxylation.
D000284:Administration, Oral; D000328:Adult; D000639:Amitriptyline / Q000097:blood / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D019389:Cytochrome P-450 CYP2D6; D003647:Debrisoquin / Q000031:analogs & derivatives / Q000378:metabolism / Q000652:urine; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D006900:Hydroxylation; D007700:Kinetics; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D009661:Nortriptyline / Q000097:blood / Q000378:metabolism*; D010641:Phenotype
D000639:Amitriptyline; C012359:4-hydroxydebrisoquin; D009661:Nortriptyline; D006899:Mixed Function Oxygenases; D019389:Cytochrome P-450 CYP2D6; D003647:Debrisoquin