Abstract
The metabolism of nortriptyline was studied in vitrousing cDNA-expressed human cytochrome P450 isozymes 1A2, 3A4, 2C19, and 2D6. CYP2D6 was the sole isozyme mediating hydroxylation of nortriptyline, the quantitatively most important metabolic pathway, and only (E)-10-OH-nortriptyline was formed. CYP2D6, 2C19, and 1A2, mentioned in decreasing order of significance, mediated the demethylation reaction of nortriptyline, whereas 3A4 did not participate in the metabolism of nortriptyline.
Concerning the quantitative relations, CYP2D6 exhibited a high affinity with respect to hydroxylation and demethylation (Km 0.48–0.74 μmol/l), a high hydroxylation capacity (Vmax 130 mol/hr/mol CYP) and a somewhat lower demethylation capacity (Vmax 19 mol/hr/mol CYP). The affinities of 1A2 and 2C19 were 100-fold lower (Km54–118 μmol/l). The capacity of 1A2 was low (Vmax 6.8 mol/hr/mol CYP), whereas 2C19 had the highest demethylation capacity (Vmax 93 mol/hr/mol CYP). Taking into account the relative amounts of CYP isozymes present in the liver, about 90% of the metabolism was estimated to depend on CYP2D6, with CYP2C19 and 1A2 mediating the remaining 10%. In subjects lacking the 2D6 isozyme, CYP2C19 and 1A2 are expected to be of major importance for elimination of nortriptyline.
Footnotes
-
Send reprint requests to: Ole V. Olesen, Ph.D. Institute for Basic Psychiatric Research, Department of Biological Psychiatry, Psychiatric Hospital in Aarhus, Aarhus University Hospital, DK-8240 Risskov, Denmark.
-
This work has been supported by The Psychiatric Research Foundation, The Lundbeck Foundation, Jacob Madsen’s Foundation, and Albert Nielsen’s Foundation.
- Abbreviations used are::
- CYP2D6
- cytochrome P450 2D6 isozyme
- P450
- cytochrome P450
- Received December 13, 1996.
- Accepted March 6, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
DMD articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|