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 omeprazole 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 (AUC0–12h) 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 kinetics between the genotypes appears unlikely.
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Acknowledgements
We acknowledge research nurses Peter Johansson and Ilona Skilving, for excellent assistance at the Human Pharmacology Unit, Karolinska University Hospital, Huddinge, and Drs. Erik Sparve and Ylva Böttiger for additional help with study subjects. This work was supported by grants from the Swedish Research Council (5949 and 3902), the Stockholm County Council (ALF 20050551/20060420), The Danish Agency for Science, Technology and Innovation, The Lundbeck Foundation, Torsten och Ragnar Söderbergs stiftelse, and by a research stipend in clinical pharmacology from Pfizer Sweden AB. EE is employed by AstraZeneca R&D Södertälje, but this work was designed and carried out as independent academic research within the Karolinska Institutet.
Conflicts of interest
The authors have no conflicts of interest to report. One author (RSP) was partly financed by an unrestricted grant by the Lundbeck Foundation, but he did not participate in the planning of these studies, only in the omeprazole analyses.
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Ohlsson Rosenborg, S., Mwinyi, J., Andersson, M. et al. Kinetics of omeprazole and escitalopram in relation to the CYP2C19*17 allele in healthy subjects. Eur J Clin Pharmacol 64, 1175–1179 (2008). https://doi.org/10.1007/s00228-008-0529-z
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DOI: https://doi.org/10.1007/s00228-008-0529-z