RT Journal Article SR Electronic T1 Hydroxylation and Demethylation of the Tricyclic Antidepressant Nortriptyline by cDNA-Expressed Human Cytochrome P-450 Isozymes JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP 740 OP 744 VO 25 IS 6 A1 Ole V. Olesen A1 Kristian Linnet YR 1997 UL http://dmd.aspetjournals.org/content/25/6/740.abstract AB 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. The American Society for Pharmacology and Experimental Therapeutics