Rates of in vivo methylation of desipramine and nortriptyline.
Routine monitoring of an 81-year-old man receiving treatment with nortriptyline for generalized anxiety disorder and depression revealed plasma concentrations of both amitriptyline and nortriptyline. In humans, the tricyclic antidepressant (TCA) tertiary amines imipramine and amitriptyline are typically metabolized by demethylation to the secondary active metabolites desipramine and nortriptyline, respectively. However, to our knowledge, methylation of secondary amine TCAs has been reported in only one case report of nortriptyline overdose and in two studies involving desipramine. In a retrospective analysis of patients from five Veterans Affairs medical centers, the rate of methylation of desipramine and nortriptyline was 8.9 % (five of 56 patients) and 14.6% (36 of 247), respectively. Possible explanations for methylation include genetic polymorphisms in cytochrome P450 metabolizing enzymes, polymorphism of amine N-methyltransferase enzyme, drug-drug interactions, smoking, and alcohol consumption. However, the mechanism by which methylation occurs is unclear and warrants further investigation. Awareness of the phenomenon could help in discouraging repeated laboratory tests and unnecessary adjustments of drug therapies, resulting in cost savings and better patient outcomes.
College of Pharmacy, University of Iowa, Iowa City, Iowa 52246, USA.
Molly P
MP
Kurpius
Bruce
B
Alexander
D000369:Aged, 80 and over; D000929:Antidepressive Agents, Tricyclic / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D001008:Anxiety Disorders / Q000188:drug therapy* / Q000201:enzymology; D019175:DNA Methylation / Q000187:drug effects; D003866:Depressive Disorder / Q000188:drug therapy* / Q000201:enzymology; D003891:Desipramine / Q000493:pharmacokinetics* / Q000627:therapeutic use; D016903:Drug Monitoring; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics* / Q000627:therapeutic use; D006801:Humans; D008297:Male; D008780:Methyltransferases / Q000187:drug effects; D009661:Nortriptyline / Q000493:pharmacokinetics* / Q000627:therapeutic use; D012189:Retrospective Studies
D000929:Antidepressive Agents, Tricyclic; D004791:Enzyme Inhibitors; D009661:Nortriptyline; D008780:Methyltransferases; D003891:Desipramine