Abstract
After 3 weeks' nortriptyline (NT) treatment the mean plasma concentration of its 10-hydroxy metabolite (10-OH-NT) (599 +/- 207 nmol l-1) was higher than that of the parent drug (433 +/- 199 nmol l-1) in 25 depressed patients. Also in the cerebrospinal fluid (CSF) the mean level of 10-OH-NT (67 +/- 20 nmol l-1) was higher than that of NT (39 +/- 23 nmol l-1). There was a strong correlation (P less than 0.001) between the CSF and plasma concentration of both NT (r = 0.92) and 10-OH-NT (r = 0.77). The interindividual variation in the CSF/plasma ratio of both compounds was small, compared to the variation in plasma levels. These results show that 10-OH-NT passes the blood-brain barrier as it is present in concentrations higher than those of NT in the CSF. 10-OH-NT has previously been shown to be a potent blocker of noradrenaline uptake and to have much less affinity for muscarinic receptors than NT itself. This active metabolite might therefore be a potential antidepressant with less disturbing anticholinergic side-effects.
Full text
PDF
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Asberg M., Cronholm B., Sjöqvist F., Tuck D. Correlation of subjective side effects with plasma concentrations of nortriptyline. Br Med J. 1970 Oct 3;4(5726):18–21. doi: 10.1136/bmj.4.5726.18. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Asberg M., Crönholm B., Sjöqvist F., Tuck D. Relationship between plasma level and therapeutic effect of nortriptyline. Br Med J. 1971 Aug 7;3(5770):331–334. doi: 10.1136/bmj.3.5770.331. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Bertilsson L., Mellström B., Sjöqvist F. Pronounced inhibition of noradrenaline uptake by 10-hydroxymetabolites of nortriptyline. Life Sci. 1979 Oct 8;25(15):1285–1292. doi: 10.1016/0024-3205(79)90393-x. [DOI] [PubMed] [Google Scholar]
- Feighner J. P., Robins E., Guze S. B., Woodruff R. A., Jr, Winokur G., Munoz R. Diagnostic criteria for use in psychiatric research. Arch Gen Psychiatry. 1972 Jan;26(1):57–63. doi: 10.1001/archpsyc.1972.01750190059011. [DOI] [PubMed] [Google Scholar]
- Kragh-Sorensen P., Hansen C. E., Baastrup P. C., Hvidberg E. F. Self-inhibiting action of nortriptylin's antidepressive effect at high plasma levels: a randomized double-blind study controlled by plasma concentrations in patients with endogenous depression. Psychopharmacologia. 1976 Feb 2;45(3):305–312. doi: 10.1007/BF00421145. [DOI] [PubMed] [Google Scholar]
- Mellström B., Bertilsson L., Säwe J., Schulz H. U., Sjöqvist F. E- and Z-10-hydroxylation of nortriptyline: relationship to polymorphic debrisoquine hydroxylation. Clin Pharmacol Ther. 1981 Aug;30(2):189–193. doi: 10.1038/clpt.1981.147. [DOI] [PubMed] [Google Scholar]
- Piafsky K. M., Borgå O. Plasma protein binding of basic drugs. II. Importance of alpha 1-acid glycoprotein for interindividual variation. Clin Pharmacol Ther. 1977 Nov;22(5 Pt 1):545–549. doi: 10.1002/cpt1977225part1545. [DOI] [PubMed] [Google Scholar]
- Sjöqvist F., Bertilsson L., Asberg M. Monitoring tricyclic antidepressants. Ther Drug Monit. 1980;2(1):85–93. doi: 10.1097/00007691-198001000-00010. [DOI] [PubMed] [Google Scholar]
- Wägner A., Ekqvist B., Bertilsson L., Sjöqvist F. Weak binding of 10-hydroxymetabolites of nortriptyline to rat brain muscarinic acetylcholine receptors. Life Sci. 1984 Sep 24;35(13):1379–1383. doi: 10.1016/0024-3205(84)90395-3. [DOI] [PubMed] [Google Scholar]