Summary
Only small amounts of unconjugated dothiepin (unchanged drug) and northiaden were excreted in urine over a 72 hr period. More than 10% of the dose was excreted as conjugated dothiepin and less than 0.8% of the dose as conjugated northiaden. Conjugated dothiepin was thus found to be an important metabolite of dothiepin.
Conjugated dothiepin and northiaden were hydrolyzed with β-glucuronidase, and their hydrolysis inhibited with 1,4 saccharolactone. Conjugated dothiepin and northiaden were found to be a quarternary ammonium-linked glucuronide and a tertiary N-glucuronide, respectively.
Dothiepin (tertiary amine) was found to have a higher affinity to UDP-glucuronyltransferase than northiaden (secondary amine).
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Rees J.A. (1981): Clinical interpretation of pharmacokinetic data on dothiepin hydrochloride (dosulepin, prothiaden). J. Int. Med. Res.,9, 98–102.
Porter C.C., Arison B.H., Gruber V.F., Titus D.C. and Vandenheuvel W.J.A. (1975): Human metabolism of cyproheptadine. Drug Metab. Dispos.,3, 189–197.
Lehman J.P., Fenselau C. and Depaulo J.R. (1983): Quaternary ammonium-linked glucuronides of amitriptyline, imipramine and chlorpromazine. Drug Metab. Dispos.,11, 221–225.
Bahr C.V. (1971): Spectral studies on the interaction of imipramine and some of its oxidized metabolites with rat liver microsomes. Xenobiotica,1, 69–78.
Bickel M.H., Steele J.W. (1974): Binding of basic and acidic drugs to rat tissue subcellular fractions. Chem. Biol. Interactions,8, 151–162.
Bickel M.H. (1975): Binding of chlorpromazine and imipramine to red cell, albumin, lipoproteines and other blood components. J. Pharm. Pharmacol.,27, 733–738.
Gram L.F. (1977): Factors influencing the metabolism of tricyclic antidepressants. Danish Medical Bulletin,24, 81–89.
Vandel B., Sando M., Vandel S., Allers G. and Vandel R. (1982): Biotransformation of amitriptyline in depressive patients. Eur. J. Clin. Pharmacol.,22, 239–245.
Ziegler V.E., Biggel J.T., Ardekani A.B. and Rosen S.H. (1978): Contribution to the pharmacokinetics of amitriptyline. J. Clin. Pharmacol.,18, 462–467.
Gram L.F., Kofod B., Christiansen J. and Rafaelsen O.J. (1971): Imipramine metabolism: pH-dependent distribution and urinary excretion. Clin. Pharmacol. Ther.,12, 239–244.
Nies A., Robinson D.S., Friedman M.J., Green R., Cooper T.B., Ravaries and Ives J.O. (1977): Relationship between age and tricyclic anti-depressant plasma levels. Am. J. Psychiatry,134, 790–793.
Herrmann B., Schindler W. and Pulver R. (1959): Papierchro matographisher Nachweis Von Stoffwechselprodukten des tofranil. Med. Exp.,1, 381–385.
Fishman V. and Goldenberg H. (1962): Identification of a new metabolite of imipramine. Proc. Soc. Exp. Biol.,110, 187–190.
Herrmann B and Pulver R. (1960): Der Stoffwechsel des Psychopharmakons Tofranil. Arch. int. Pharmacodyn.,126, 454–469.
Hucker H.B. and Porter C.C. (1961): Studies on the metabolism of amitriptyline. Fed. Proc.,20, 172.
Eshenhof E. and Rieder J. (1969): Untersuchungen über das Schicksal des Antidepressivums Amitriptyline im Oranimus der Ratte und des Menschen. Arzneim.-Forsh.,19, 957–966.
Hucker H.B. (1962): Metabolism of amitriptyline. Pharmacologist,4, 171.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Kawahara, K., Awaji, T., Uda, K. et al. Urinary excretion of conjugates of dothiepin and northiaden (mono- N-demethyl-dothiepin) after an oral dose of dothiepin to humans. European Journal of Drug Metabolism and Pharmacokinetics 11, 29–32 (1986). https://doi.org/10.1007/BF03189772
Received:
Issue Date:
DOI: https://doi.org/10.1007/BF03189772