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Institute for Basic Psychiatric Research, Department of Biological
Psychiatry, Psychiatric Hospital in Aarhus, Aarhus University Hospital
The metabolism of nortriptyline was studied in vitro
using 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 (Km
54-118 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.
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