Heterozygous Mutation in CYP2C19 Significantly Increases the Concentration/Dose Ratio of Racemic Citalopram and Escitalopram (S-citalopram) (original) (raw)
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Pharmacokinetics of Citalopram in Relation to Genetic Polymorphism of CYP2C19
Drug Metabolism and Disposition, 2003
The study was designed to define the contribution of cytochrome P450 2C19 (CYP2C19) and cytochrome P450 3A4 (CYP3A4) to citalopram N-demethylation and to evaluate the relationship between the disposition of citalopram and CYP2C19 genotype. A single oral 40-mg dose of citalopram was administered to eight extensive metabolizers and five poor metabolizers recruited from 77 healthy Chinese volunteers whose genotypes and phenotypes were predetermined. The plasma concentrations of citalopram and desmethylcitalopram were determined by high-performance liquid chromatography. It was found that the genotype of CYP2C19 had a significant effect on the N-demethylation of citalopram. Poor metabolizers with m1 mutation had higher area under the plasma concentration versus time curve (AUC 03ؕ) values than did extensive metabolizers. Terminal elimination half-life (t 1/2) values of citalopram in poor metabolizers were significantly higher than the values in extensive metabolizers who were either homozygous or heterozygous with CYP2C19*1. The oral clearance (CL oral) of citalopram in poor metabolizers was significantly lower than that of extensive metabolizers. The AUC 03ؕ and maximum plasma concentration (C max) of desmethylcitalopram in poor metabolizers were significantly lower than the values of extensive metabolizers. The results show that CYP3A4 is not the major enzyme in the N-demethylation of citalopram among extensive metabolizers. The polymorphism of CYP2C19 plays an important role in the Ndemethylation of citalopram in vivo. The extensive metabolizers and poor metabolizers of CYP2C19 had significant difference in disposition of citalopram in vivo.
European Journal of Pharmacology, 2010
We investigate the impact of sex and genotype on citalopram disposition in 35 healthy volunteers who received an oral dose of 20 mg citalopram within a single-dose bioequivalence study. CYP2C19⁎2 and ⁎3, and CYP2D6⁎4 mutations were determined by Real-Time PCR. The influence of sex and genotype was analyzed by a linear mixed model for repeated measures, including formulation, period, sequence, sex, CYP2C19 and CYP2D6 as fixed effects and subject nested sequence⁎sex⁎CYP2C19⁎CYP2D6 as the random one. Pharmacokinetic parameters were log-transformed and AUC ∞ and C max adjusted to the administered dose/ weight. The model yields a statistical significance in AUC ∞ and CL/F for CYP2C19 and CYP2D6. Gender, formulation, sequence or period effects were not statistically significant. AUC ∞ of CYP2C19⁎1/⁎2 and CYP2C19⁎2/⁎2 carriers is 44% and 118% higher than wild type, respectively; CYP2D6 volunteers carrying ⁎1/⁎4 have an AUC 23% higher than wild type. Our data also suggest that the influence of CYP2D6 on AUC ∞ is very low when it is in association with CYP2C19⁎1/⁎1 while its influence is more apparent in association with CYP2C19⁎1/⁎2. In conclusion, we demonstrate the influence of CYP2C19 and CYP2D6 in the disposition of citalopram, and we suggest that the influence of CYP2D6 is more probable in volunteers with at least one defective allele of CYP2C19.
Identification of a Novel CYP2C19-Mediated Metabolic Pathway of S-Citalopram in Vitro
Drug Metabolism and Disposition, 2009
S substrate concentration; K m Michaelis-Menten constant; CL int intrinsic clearance; K si substrate inhibition constant; HPLC high performance liquid chromatography; UPLC ultra performance liquid chromatography; MS mass spectrometry; MS/MS tandem mass spectrometry; MRM multiple reaction monitoring; TDM therapeutic drug monitoring; t time; k depletion rate constant; A Hill coefficient; m/z mass to charge ration; N/A not applicable, V volt; eV electronvolt; kV kilovolt; mbar millibar This article has not been copyedited and formatted. The final version may differ from this version.
Omeprazole preferentially inhibits the metabolism of (+)-(S)-citalopram in healthy volunteers
British Journal of Clinical Pharmacology, 2010
• Citalopram (CITA) pharmacokinetics are enantioselective in healthy volunteers and the metabolism of (+)-(S)-CITA to (+)-(S)-DCITA is dependent on CYP2C19. Omeprazole is a potent CYP2C19 inhibitor. WHAT THIS STUDY ADDS • This study indicates that omeprazole induces a loss of enantioselectivity in the CITA pharmacokinetics because of the selective inhibition of (+)-(S)-CITA metabolism. AIM The study assessed the influence of omeprazole on the kinetic disposition of the (+)-(S)-citalopram (CITA) and (-)-(R)-CITA enantiomers in healthy volunteers. RESULTS The kinetic disposition of CITA was enantioselective in the absence of treatment with omeprazole, with the observation of a greater proportion of plasma (-)-(R)-CITA [AUC S : R ratio of 0.53 (95% CI 0.41, 0.66) for CITA and 1.08 (95% CI 0.80, 1.76) for DCITA] than (+)-(S)-CITA. Racemic CITA administration to healthy volunteers in combination with omeprazole showed a loss of enantioselectivity in CITA pharmacokinetics with an increase of approximately 120% in plasma (+)-(S)-CITA concentrations [AUC S : R ratio of 0.95 (95% CI 0.72, 1.10) for CITA and 0.95 (95% CI 0.44, 1.72) for DCITA]. CONCLUSIONS The administration of multiple doses of omeprazole preferentially inhibited (+)-(S)-CITA metabolism in healthy volunteers. Although omeprazole increased plasma concentrations of (+)-(S)-CITA by approximately 120%, it is difficult to evaluate the clinical outcome because the range of plasma CITA concentrations related to maximum efficacy and minimum risk of adverse effects has not been established.
Effects of Polymorphisms in CYP2D6, CYP2C9, and CYP2C19 on Trimipramine Pharmacokinetics
Journal of Clinical Psychopharmacology, 2003
Little is known about the impact of cytochrome P450 polymorphisms on the metabolism of trimipramine, which is still widely used as antidepressant due to its positive effect on sleep patterns. A single oral dose of 75 mg trimipramine was given to 42 healthy volunteers selected according to their CYP2D6, CYP2C19, and CYP2C9 genotypes. The reference group included 8 subjects with homozygous active wild-type genotypes of all 3 enzymes (EM). This group was compared with 7 intermediate (IM) with 1 and 7 poor metabolizers (PM) with zero active alleles of CYP2D6 and CYP2C19, respectively, and with 4 subjects with the genotype CYP2C9*3/*3. Pharmacokinetics of trimipramine and its demethylated metabolite strongly depended on the CYP2D6 genotype. Median oral clearance of trimipramine was 276 L/h (range 180-444) in the reference group but only 36 L/h (range 24-48) in CYP2D6 PMs (P < 0.001). These differences could only be explained by an effect of CYP genotypes on both parameters, systemic clearance and bioavailability, the latter being at least 3-fold higher in CYP2D6 PMs than in the reference group. The desmethyltrimipramine area under the concentration-time curve was 40-fold greater in CYP2D6 PMs than in the reference group (1.7 vs. 0.04 mg/LÁh in EMs), but below the quantification limit in most carriers of deficiencies of CYP2C19 or CYP2C9. This indicates that both CYP2C enzymes contribute to the demethylation of desmethyltrimipramine and CYP2D6 to further metabolism.
Journal of Analytical Toxicology, 2004
Citalopram, a selective serotonin reuptake inhibitor, is one of the most commonly found drugs in Swedish forensic autopsy cases. Citalopram is a racemic drug with 50:50 of the S-and Renantiomers. Enantioselective analysis of citalopram and its metabolites desmethylcitalopram and didesmethylcitalopram were performed in femoral blood from 53 autopsy cases by a chiral highperformance liquid chromatography (HPLC) method. The mean (• standard deviation) S/R ratio for citalopram was 0.67 • 0.25 and for desmethylcitalopram, 0.68 • 0.20. We found increasing S/R ratios with increasing concentrations of citalopram. We also found that high citalopram S/R ratios were associated with a high parent drug-to-metabolite ratio and may be an indicator of recent intake. Citalopram is metabolized by cytochrome P450 (CYP) 3A4, 2C19, and 2D6. Genotyping for the polymorphic CYP2C19 and CYP2D6 revealed no poor metabolizers regarding CYP2C19 and only 2 (3.8%) poor metabolizers regarding CYP2D6. The presence of drugs metabolized by and/or inhibiting these enzymes in several of the cases suggests that such pharmacokinetic interactions are a more important (practical) problem than metabolic deficiency. Enantioselective analysis of citalopram and its metabolites can provide additional information when interpreting forensic toxicology results and might be a necessity in the future.
Journal of Analytical Toxicology, 2004
Citalopram, a selective serotonin reuptake inhibitor, is one of the most commonly found drugs in Swedish forensic autopsy cases. Citalopram is a racemic drug with 50:50 of the S-and Renantiomers. Enantioselective analysis of citalopram and its metabolites desmethylcitalopram and didesmethylcitalopram were performed in femoral blood from 53 autopsy cases by a chiral highperformance liquid chromatography (HPLC) method. The mean (• standard deviation) S/R ratio for citalopram was 0.67 • 0.25 and for desmethylcitalopram, 0.68 • 0.20. We found increasing S/R ratios with increasing concentrations of citalopram. We also found that high citalopram S/R ratios were associated with a high parent drug-to-metabolite ratio and may be an indicator of recent intake. Citalopram is metabolized by cytochrome P450 (CYP) 3A4, 2C19, and 2D6. Genotyping for the polymorphic CYP2C19 and CYP2D6 revealed no poor metabolizers regarding CYP2C19 and only 2 (3.8%) poor metabolizers regarding CYP2D6. The presence of drugs metabolized by and/or inhibiting these enzymes in several of the cases suggests that such pharmacokinetic interactions are a more important (practical) problem than metabolic deficiency. Enantioselective analysis of citalopram and its metabolites can provide additional information when interpreting forensic toxicology results and might be a necessity in the future.
Drugs & Aging
Background Many drugs with dose-dependent effects on hemodynamic variables are metabolized by cytochrome P450 2D6 (CYP2D6). The aim of this study was to compare prescribed dosages and hemodynamic responses of such drugs in relation to pharmacogenetic variability in CYP2D6 metabolism among patients aged ≥ 70 years exposed to polypharmacy. Materials and Methods We included 173 patients with detailed information about drug use. The patients were retrospectively subjected to CYP2D6 genotyping, which comprised the most common variant alleles encoding reduced, absent, or increased CYP2D6 metabolism. In order to compare dosages across different CYP2D6-metabolized drugs, all prescribed daily doses were harmonized to the 'percent of a daily defined dose' (DDD). The mean harmonized DDD was compared between genotype-predicted normal metabolizers (NMs) and patients with reduced or absent CYP2D6 enzyme activity, defined as intermediate or poor metabolizers (IMs/PMs). Blood pressure, pulse, and patient proportions with orthostatism and bradycardia were also compared between genotype subgroups. Results The genotype-predicted phenotype subgroups comprised 79 NMs (45.7%), 75 IMs (43.4%), and 16 PMs (9.2%). There were no differences in dosing of CYP2D6 substrates between NMs and IMs/PMs (p = 0.76). A higher proportion of CYP2D6 IMs/PMs experienced orthostatism (p = 0.03), while there were no significant subgroup differences for the other hemodynamic variables. Conclusion In this real-life clinical setting of patients aged ≥ 70 years, dosing of CYP2D6 substrates were not adjusted according to genotype-predicted CYP2D6 metabolism. The increased occurrence of orthostatism in patients with reduced/ absent CYP2D6 metabolism may indicate that individualized dosing based on genotype has the potential to prevent adverse effects in these vulnerable patients.
Estimation of Drug-Metabolizing Capacity by Cytochrome P450 Genotyping and Expression
Journal of Pharmacology and Experimental Therapeutics, 2012
Many undesired side-effects or therapeutic failures of drugs are the results of differences or changes in drug-metabolism, primarily depending on the levels and activities of cytochrome P450 (CYP) enzymes. In order to assess whether CYP-expression profiles can reflect the hepatic drug-metabolism, we compared CYP mRNA levels in the liver or in peripheral leukocytes with the corresponding hepatic CYP-activities. A preliminary CYP-genotyping for the most frequent polymorphisms in Caucasian populations (CYP2C9*2, CYP2C9*3, CYP2C19*2, CYP2C19*3, CYP2D6*3, CYP2D6*4, CYP2D6*6 and CYP3A5*3) was carried out before CYP-phenotyping, excluding the donors with non-functional alleles of CYP2C9, CYP2C19 and CYP2D6, and those with functional CYP3A5*1 allele from a correlation analysis. The hepatic mRNA levels of CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6 and CYP3A4 displayed a strong association with CYP-activities in the liver, whereas the expression of CYP1A2, CYP2C9, CYP2C19 and CYP3A4 in leukocytes was proven to reflect the hepatic activities of these CYP species. The leukocytes were found to be inappropriate cells for the assessment of hepatic CYP2B6 and CYP2D6 activities. Combining the results of CYP-genotyping and CYP-phenotyping analyses, patients' drug-metabolizing capacities can be estimated by the CYP-expression in the liver and also in leukocytes, with some limitations. Patients' genetic and non-genetic variations in CYP-status can guide the appropriate selection of drugs and the optimal dose, minimizing the risk of harmful sideeffects and ensuring a successful outcome of drug therapy.