The impact of CYP2C19 polymorphisms on citalopram metabolism in patients with major depressive disorder.
OBJECTIVE
Genetic variations in drug-metabolizing enzyme genes change drug pharmacokinetics and response. CYP2C19 is a clinically important enzyme that metabolizes citalopram (CIT). The objective of this study was to determine CYP2C19 genetic polymorphisms and to evaluate the impact of these polymorphisms on the metabolism of citalopram in a sample of the Turkish population. We also assessed *17 polymorphism in healthy subjects in this population.


METHODS
The CYP2C19 genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism method (209 healthy individuals and 50 patients for CIT metabolism), and the plasma concentrations of CIT and demethylcitalopram (DCIT) were quantified by high-performance liquid chromatography.


CONCLUSIONS
The CYP2C19*1 and *17 allele frequencies for the patient group and the healthy group were 71·0%, 18·0% and 81·1%, 18·9%, respectively. There was no significant difference between the two groups (P > 0·05). The mean plasma concentrations and the mean dose-corrected (C/D) plasma levels of DCIT were significantly higher in patients with the CYP2C19*1/*1 genotype compared to patients with CYP2C19*1/*2 and CYP2C19*2/*2 genotypes (P < 0·05). Furthermore, the mean metabolic ratio (MR, CIT/DCIT) was also significantly higher in the CYP2C19*1/*2 + CYP2C19*2/*2 genotypes (P < 0·05). On the other hand, plasma CIT, DCIT concentrations and M/R value in the CYP2C19*1/*1 genotypes were no different to those of the CYP2C19*1/*17 genotypes (P > 0·05).


CONCLUSIONS
Our data suggest that CYP2C19*17 polymorphism does not have a significant effect on CIT metabolism. In contrast CYP2C19*2 polymorphism has a prominent role and is likely to contribute to interindividual variability in CIT metabolism in vivo at therapeutic doses.
Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Mersin University, Mersin, Turkey.
Z
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Uckun
Psychiatry Department, School of Medicine, Ankara University, Ankara, Turkey.
B
B
Baskak
Psychiatry Department, School of Medicine, Ankara University, Ankara, Turkey.
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ET
Ozel-Kizil
Department of Psychiatry, Faculty of Medicine, Kirikkale University, Kirikkale, Turkey.
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H
Ozdemir
Psychiatry Department, School of Medicine, Ankara University, Ankara, Turkey.
H
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Devrimci Ozguven
Department of Toxicology, Faculty of Pharmacy, Ankara University, Ankara, Turkey.
H S
HS
Suzen
D000328:Adult; D000368:Aged; D015283:Citalopram / Q000031:analogs & derivatives / Q000378:metabolism* / Q000627:therapeutic use*; D065731:Cytochrome P-450 CYP2C19 / Q000235:genetics*; D003865:Major Depressive Disorder / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic / Q000235:genetics*
C514709:demethylcitalopram; D015283:Citalopram; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19
CYP2C19; citalopram; genetic polymorphisms; major depressive disorder