PHARMACOGENETICS
Kinetics of omeprazole and escitalopram in relation
to the CYP2C19*17 allele in healthy subjects
Staffan Ohlsson Rosenborg
&
Jessica Mwinyi
&
Maria Andersson
&
R. Michael Baldwin
&
Rasmus Steen Pedersen
&
Sarah C. Sim
&
Leif Bertilsson
&
Magnus Ingelman-Sundberg
&
Erik Eliasson
Received: 8 February 2008 / Accepted: 19 June 2008 / Published online: 25 July 2008
#
Springer-Verlag 2008
Abstract
Purpose Ultrarapid drug metabolism of antidepressants has
been associated with therapeutic failures. The CYP2C19*17
allele has been associated with higher levels of CYP2C19
gene transcription and increased rates of omeprazole and
mephenytoin metabolism. The aim of this study was to
compare the impact of the CYP2C19*17 allele on omepra-
zole single-dose kinetics with escitalopram exposure at steady
state in volunteers genotyped as either CYP2C19*17/*17 or
CYP2C19*1/*1.
Methods Sixteen healthy volunteers participated in both
study parts, five homozygous for CYP2C19*17 and 11
homozygous for CYP2C19*1. Individual pharmacokinetic
parameters were determined after single-dose omeprazole
of 40 mg and after 1 week on escitalopram 5 mg b.i.d.
Results Escitalopram area under the concentration time
curve from zero to 12 h (AUC
0–12h
) was 21% lower in
homozygous carriers of CYP2C19*17 compared with
CYP2C19*1 (p=0.08). There was a significant correlation
between escitalopram exposure at steady state and the
single-dose kinetics of omeprazole (Spearman correlation
coefficient of 0.67; p=0.006).
Conclusion Based on our investigation using two different
CYP2C19 substrates, we concluded that a clinically
significant difference in escitalopram or omeprazole kinet-
ics between the genotypes appears unlikely.
Keywords Pharmacokinetics
.
Pharmacogenetics
.
Antidepressants
.
Poor responders
.
Therapeutic failure
.
Serotonin uptake inhibitor
.
Drug metabolism
Introduction
CYP2C19 is an important enzyme in the hepatic metabo-
lism of many drugs, including antidepressants [1]. Recently,
we described a novel allelic variant of the CYP2C19 gene,
CYP2C19*17, that was associated with increased levels of
CYP2C19 gene expression. Retrospective genotype analysis of
CYP phenotyped Swedes and Ethiopian volunteers indicated
that this allele is quite common (18% frequency in both
populations) and that homozygous carriers of CYP2C19*17
metabolized mephenytoin and omeprazole, two phenotypic
probe drugs of CYP2C19 in vivo, more rapidly than
heterozygous or homozygous carriers of CYP2C19*1 [2].
The metabolism of omeprazole is to a great extent
catalysed by CYP2C19 to yield 5-hydroxyomeprazole,
whereas sulphoxidation of omeprazole is catalysed by
CYP3A4 [3]. The 5-hydroxylation is an important reaction
for omeprazole clearance and, indeed, we recently obtained
conclusive evidence from omeprazole single-dose kinetics
experiments that the mean systemic clearance of omepra-
zole is 21% higher in homozygous carriers of CYP2C19*17
compared with CYP2C19*1 [4].
Citalopram, together with its active enantiomer escitalo-
pram, is a leading antidepressant in the Nordic countries. In
Eur J Clin Pharmacol (2008) 64:1175–1179
DOI 10.1007/s00228-008-0529-z
S. Ohlsson Rosenborg (*)
:
M. Andersson
:
L. Bertilsson
:
E. Eliasson
Karolinska Institutet, Department of Laboratory Medicine,
Division of Clinical Pharmacology,
Karolinska University Hospital Huddinge,
SE-141 86 Stockholm, Sweden
e-mail: staffan.ohlsson@ki.se
J. Mwinyi
:
R. M. Baldwin
:
R. S. Pedersen
:
S. C. Sim
:
M. Ingelman-Sundberg
Department of Physiology and Pharmacology,
Section of Pharmacogenetics, Karolinska Institutet,
Stockholm, Sweden