Molecular and Cellular PharmacologyEvaluation of the influence of sex and CYP2C19 and CYP2D6 polymorphisms in the disposition of citalopram
Introduction
Individual differences in drug metabolism are a major contributor to variability in drug response (Wilkinson, 2005). Cytochromes P450 2C19 (CYP2C19) and P450 2D6 (CYP2D6) are important enzymes involved in the metabolism of several antidepressants; and other factors such as age, gender or use of interacting drugs are potential contributors to variability in their activity (Desta et al., 2002).
Citalopram is a frequently used antidepressant, representative of the class of selective serotonin reuptake inhibitors (SSRIs). Citalopram is marketed as a racemate, but its pharmacological effects are almost exclusively ascribed to the S-(+) enantiomer (Hyttel, 1992). Absorption of citalopram from the gastrointestinal tract is almost complete. Citalopram is initially demethylated to its metabolite desmethylcitalopram, which also acts as a SSRI. Desmethylcitalopram may amount to about 40% of the mean parent drug at steady-state plasma concentration, with large interindividual variability, and its in vitro reuptake inhibitory potency is tenfold lower than citalopram. Desmethylcitalopram is further demethylated to didesmethylcitalopram, which retains weak serotonin reuptake inhibiting activity and reaches lower concentrations than the parent drug and its main metabolite in human plasma (Milne and Goa, 1991). In addition, citalopram metabolites have poor blood–brain barrier penetration. Therefore, metabolites are not thought to contribute to the therapeutic action of citalopram.
In vitro studies (Kobayashi et al., 1997, Rochat et al., 1995, Olesen and Linnet, 1999) have shown that citalopram metabolism is dependent on several cytochrome CYP isoenzymes. Primarily, CYP2C19 and CYP3A4 contribute to the formation of desmethylcitalopram and CYP2D6 in the demethylation of desmethylcitalopram to didesmethylcitalopram. Nevertheless, only CYP2C19 has been clearly demonstrated to contribute to citalopram N-demethylation in “in vivo” studies. Thus, CYP2C19 poor metabolizers (PM) are reported to achieve higher systemic exposure of citalopram than CYP2C19 extensive metabolizers (EM) (Sindrup et al., 1993).
Gender influence on CYP2C19 activity is controversial, since some studies performed with patients have shown no gender-based differences while others show higher activity in males (Scandlyn et al., 2008). In the case of citalopram, the influence of gender on its disposition is also controversial. Leinonen et al., 1996, de Mendonça Lima et al., 2005 did not find differences in plasma levels of citalopram between males and females. On the other hand, higher dose-corrected concentrations of citalopram (18%) and desmethylcitalopram (25%), and lower citalopram clearance values (14%) were found in women compared to men (Reis et al., 2003). Another study (Le Bloc'h et al., 2003) found significantly higher concentrations in men than in women when administered doses were 70–200 mg/day, but not when patients were treated with 10–60 mg/day. These discrepancies could be attributed to factors such as the design of these studies, or to weight adjustments of the dose.
The objective of this study was to investigate the impact of gender and genetic variations in CYP2C19 and CYP2D6 on the disposition of citalopram in healthy volunteers in a bioequivalence study.
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Subjects
Thirty-six healthy, non-smoking male and female Spanish subjects, with a mean age of 25 years (range 21–33 years) and a mean weight of 67 kg (range 53–90 kg), were enrolled. Before enrolment, each subject was shown to be in good health through medical history, physical examination, ECG, and routine laboratory tests. No medication was used for at least 2 weeks before the study, including contraceptive medications, and alcohol was forbidden within 72 h prior to drug administration. Drugs of abuse
Results
Both formulations were found bioequivalent after the standard bioequivalence statistical analysis. No period, sequence or formulation effects were found.
Demographic and genotypic characteristics of the patients included are summarized in Table 1, Table 2. As expected, males and females differ markedly in weight and therefore the dose–weight adjustment of dose-dependent parameters (AUC∞ and Cmax) is justified. No subjects with CYP2C19⁎3 variant were found. No statistical differences in the
Discussion
Here we present an evaluation of the influence of gender and genotype in the disposition and pharmacokinetic parameters of citalopram, performed within a bioequivalence study. The analysis of the influence of gender on disposition parameters of drugs within a bioequivalence trial has been shown to be useful (Borobia et al., 2009, Carcas et al., 2001) and an appropriate statistical approach has been described (Chen et al., 2000). In addition to the influence of gender, the impact of the
Conclusion
We have confirmed the influence of CYP2C19 on citalopram disposition as well as a gene–dose effect in this relationship. Also, we have reported for the first time the “in vivo” influence of CYP2D6 in the disposition of citalopram. Interestingly, our data suggest that the influence of CYP2D6 is more likely in volunteers with at least one CYP2C19-defective allele. We found no gender differences in the disposition of citalopram.
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