CYP2C19 Genetic Polymorphism
941
PM/CYP2C19 EM and 40% lower in CYP2D6
EM/CYP2C19 PM.
individuals. They found a significant mean in-
crease of 46, 128 and 113% in Cmax, AUC and half-
life, respectively, and a 55% decrease in clearance
of fluoxetine in Chinese PMs compared with EMs.
The AUC of norfluoxetine was significantly
higher in EMs than in PMs. A study by Sindrup et
Severe adverse effects of TCAs appear espe-
cially likely when both metabolic pathways are
blocked. For example, severe adverse effects have
been observed after concomitant administration of
a TCA with fluvoxamine or fluoxetine, inhibitors
[
174]
al.
indicated that the AUC, half-life and Cmax
[
304]
of both CYP2C19 and CYP2D6.
Similar ef-
of racemic citalopram (40 mg/day for 10 days)
were significantly higher in PMs of CYP2C19 than
in EMs, whereas total clearance and formation
clearance of desmethyl-citalopram were ~44% and
~56% lower in PMs than in EMs. CYP2D6 and
CYP2C19 have been implicated in the metabolism
of venlafaxine, a new antidepressant that blocks
the reuptake of serotonin, noradrenaline and dopa-
mine, to O-desmethyl-venlafaxine, which is a ma-
jor metabolic pathway and an active metabolite.
There is also evidence that moclobemide is a sub-
fects are expected when CYP2C19 inhibitors (e.g.
omeprazole)[ or CYP2D6 inhibitors (e.g. quini-
94]
[
305]
dine and many antipsychotics)
are coadmini-
stered with tertiary amine TCAs in CYP2D6 PMs
and CYP2C19 PMs, respectively. As with diaze-
pam, considerably lower dosages of antidepres-
sants, including TCAs, have been prescribed
empirically in East Asians compared with Cauca-
sians.[
306]
This practice seems to be derived, at
least in part, from the pharmacogenetic differences
between the two ethnic groups in both CYP
isoforms involved in the metabolism of these
drugs. Compared with about 3% of CYP2C19 PMs
among Caucasians, the proportion of CYP2C19
[
100]
strate of CYP2C19 in vitro,
which was later
confirmed from a study by Yu et al.,[
309]
who re-
ported significantly slower elimination of mo-
clobemide in PMs than in EMs of CYP2C19, as
well as during administration of single (40mg) and
multiple (40 mg/day for 7 days) doses of ome-
prazole to EMs.
[
37,307]
PMs in Asians is as high as 15 to 20%.
The
mean CYP2D6 activity is also lower in Asians than
Caucasians because of the higher proportion of the
CYP2D6*10 mutation, which yields lower enzyme
activity, in Asians.[
Drug interactions of antidepressants are impor-
tant because these drugs are frequently combined
with many other drugs such as antipsychotics,[
have a narrow therapeutic range (e.g. TCAs) and
may cause serious adverse effects associated with
increased drug concentrations. Table VIII summa-
rises drug interactions of antidepressants related to
CYP2C19 substrates. Cimetidine, a nonspecific
CYP inhibitor, increases the plasma concentra-
tions of the reversible MAO inhibitor moclobem-
37,308]
310]
Some of the selective serotonin reuptake inhib-
itors (SSRIs), such as citalopram, sertraline,
fluoxetine and venlafaxine, and the reversible
MAO inhibitor moclobemide are also substrates
of CYP2C19 (table IV). According to Wang et
al.,[
150]
the mean clearance of sertraline was de-
creased (~30%) and the AUC and half-life were
increased by ~41% and ~51%, respectively, in
Chinese CYP2C19 PMs compared with EMs,
whereas the mean AUC (~36%) and Cmax (~27%)
of N-desmethyl-sertraline were lower in PMs than
in EMs. In two of their PMs (but not EMs), they
noted severe gastrointestinal disturbances and in-
creased CNS effects (dry mouth and dizziness) 2
ide and of tertiary amine TCAs, but not of second-
ary amine TCAs.[
311]
TCAs appear not to strongly
inhibit the metabolism of CYP2C19 substrates.
They have no interaction with mephenytoin and
moclobemide.[
311]
However, it should be consid-
ered that minor inhibition by imipramine has been
reported to significantly increase the plasma con-
centration of phenytoin, which has saturable phar-
hours after sertraline administration. Recently, Liu
et al.[
149]
have demonstrated that CYP2C19 plays
a major role in N-demethylation of fluoxetine (sin-
gle oral 40mg dose) to norfluoxetine in Chinese
macokinetics and is metabolised mainly by CYP-
2C9 and partly by CYP2C19,[
108,312]
even though
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Clin Pharmacokinet 2002; 41 (12)