Citalopram pharmacokinetics

In 11 healthy adults citalopram 40 mg/day had no effect on the pharmacokinetics of a single oral dose of digoxin 1 mg (255). Digoxin did not affect citalopram pharmacokinetics. 

Smoking does not appear to alter citalopram pharmacokinetics, and has onfy modest effects on fluvoxamine pharmacokinetics. 

Haffen E, Vandel P, Bonin B, Vandel S. Citalopram pharmacokinetic interaction with clomipramine. UDP-glucurono ltransferase inhibition A case report Therapie (1999) 54, 768-70. 

It is perhaps not surprising that, even after taking into account pharmacokinetic differences between these drugs, the therapeutic doses of the SSRIs do not parallel their Ki for inhibition of 5-HT reuptake. For instance, citalopram is about a thousand times more selective than fluoxetine for inhibition of 5-HT uptake, and yet their clinically effective doses are similar. In short, not only is their selectivity for the 5-HT transporter in vitro a poor predictor of their efficacy in vivo but it has to be questioned whether any of these compounds actually work by blocking 5-HT uptake alone. 

Despite their common ability to enhance serotonergic function in vivo, the SSRIs differ both in terms of their pharmacological profiles and their pharmacokinetics. Thus in addition to their direct inhibitory action on the serotonin transporter, they also affect other neurotransmitter systems which may have some clinical relevance. Citalopram has a modest antihistamine action which might account for its slightly sedative action. Sertraline has a... 

Elderly Clearance of fluvoxamine is decreased by about 50% in elderly patients. A lower starting dose of paroxetine is recommended. Sertraline plasma clearance may be lower. In 2 pharmacokinetic studies, citalopram AUC was increased by 23% and 30%, respectively, in elderly subjects as compared with younger subjects, and its half-life was increased by 30% and 50%, respectively. In 2 pharmacokinetic studies, escitalopram half-life was increased by approximately 50% in elderly subjects as compared with young subjects and C ax was unchanged. 

Brookes AJ, Lehvaslaiho H, Siegfried M, et al (2000) HGBASE a database of SNPs and other variations in and around human genes. Nucleic Acids Res 28 356-360 Brosen K, Naranjo CA (2001) Review of pharmacokinetic andpharmacodynamic interaction studies with citalopram. Eur Neuropsychopharmacol 11 275-283 Brosen K, Hansen JG, Nielsen KK, Sindrup SH, Gram LF (1993) Inhibition by paroxetine of desipramine metabolism in extensive but not in poor metabolizers of sparteine. Eur J Clin Pharmacol 44 349-355... 

A more common approach in difficult to treat cases would be the combination of clomipramine with a SSRI several reports lend support to this practice (Simeon and Thatte, 1990 Figueroa et al., 1998). In this situation, careful attention to the potential pharmacokinetic interactions discussed above are recommended. Sertraline and citalopram are least likely to elevate tricyclic levels due to less potential GYP interactions. By expert consensus, second- (venlafaxine) and third-line (nefazadone and gabapentin) agents may be used when clinical response is inadequate despite a lack of controlled data. Venlafaxine may be substituted for a more typical SSRI while nefazadone or gabapentin may be added to either clomipramine or a SSRI. The combination of venlafaxine with other SSRIs is not generally recommended as it may increase the risk of a serotonin syndrome. The addition of nefazadone to SSRIs presents a lesser risk. 

Baumann P Chnical pharmacokinetics of citalopram and other selective serotonergic reuptake inhibitors (SSRIs). Int Chn Psychopharmacol 6 (suppl 5) 13-20, 1992... 

Fluvoxamine, fluoxetine, and paroxetine have nonlinear pharmacokinetics, which means that dose increases lead to disproportionately greater increases in plasma drug levels (25). In contrast, citalopram and sertraline have linear pharmacokinetics. For these reasons, dose increases with fluvoxamine, fluoxetine, and paroxetine can lead to greater than proportional increases in concentration-dependent effects such as serotonin-mediated adverse effects (e.g., nausea) and inhibition of specific CYP enzymes. 

Although venlafaxine can have more interactions than SSRIs pharmacodynamically, it is comparable with citalopram and sertraline in terms of not causing CYP enzyme mediated pharmacokinetic drug-drug interactions (Table 7-29). Thus, these three antidepressants have a distinct advantage over drugs such as fluoxetine, particularly in patients who are likely to be on other medications in aaaition to their antidepressant. 

The most common interactions with SSRIs are pharmacokinetic interactions. For example, paroxetine and fluoxetine are potent CYP2D6 inhibitors (Table 30-4). Thus, administration with 2D6 substrates such as TCAs can lead to dramatic and sometimes unpredictable elevations in the tricyclic drug concentration. The result may be toxicity from the TCA. Similarly, fluvoxamine, a CYP3A4 inhibitor, may elevate the levels of concurrently administered substrates for this enzyme such as diltiazem and induce bradycardia or hypotension. Other SSRIs, such as citalopram and escitalopram, are relatively free of pharmacokinetic interactions. The most serious interaction with the SSRIs are pharmacodynamic interactions with MAOIs that produce a serotonin syndrome (see below). 

After a 5-week washout, the 12 subjects who took citalopram in the first part of the study received 10 mg of selegiline once daily for 4 d to compare the pharmacokinetics of selegiline with and without concomitant citalopram. The safety analysis showed no significant differences in vital signs or the frequency of adverse events between the study groups. Plasma prolactin concentrations... 

Sindrup SH, Brosen K, Hansen MG, Aaes-Jorgensen T, Overo KF, Gram LF. Pharmacokinetics of citalopram in relation to the sparteine and the mephenytoin oxidation polymorphisms. Ther Drug Monit 1993 15 11-17. 

Several LC-MS and LC-MS/MS methods were developed in plasma for only one antidepressant and, sometimes, its major metabolite(s) to perform pharmacokinetic, bioavailability, or bioequivalence studies. Analytical methods developed for these purposes require very low LLOQ values and, usually, narrow linear ranges covering the low range of the therapeutic concentrations are validated. In this context, several methodologies were described for the determination of fluoxetine [94, 95, 98-100], paroxetine [44, 71, 85, 101, 102], venlafaxine [48, 61, 64, 86, 103,104], sertraline [62, 68, 83], citalopram [46, 89] and escitalopram [105], mianserine [106, 107], mirtazapine [42], trazodone [84], nefazodone [51, 81], duloxetine [47, 50, 73], and bupropion [43], Deuterated analogues of the analyte of interest or of other drugs were employed by few authors as IS [43, 61, 73, 81, 85, 99] however, in most of these methods, another antidepressant or other therapeutic drug was used for this purpose. 

Jiang T, Rong Z, Peng L et al (2010) Simultaneous determination of citalopram and its metabolite in human plasma by LC-MS/MS applied to pharmacokinetic study. J Chromatogr B Anal Technol Biomed Life Sci 878 615-619... 

Rocha A, Marques MP, Coelho EB et al (2007) Enantioselective analysis of citalopram and demethylcitalopram in human and rat plasma by chiral LC-MS/MS application to pharmacokinetics. Chirality 19 793-801... 

Hall J, Naranjo CA, Sproule BA, et al. Pharmacokinetic and pharmacodynamic evaluation of the inhibition of alprazolam by citalopram and fluoxetine. J Clin Psychopharmacol 2003 23 349-357. 

The effects of SSRIs on alprazolam pharmacokinetics have been studied in 21 healthy volunteers (age and sex not given) who were pre-treated with either fluoxetine or citalopram (20 mg/day for 21 days) (98). Fluoxetine increased the AUC of a single 1.0 mg dose of alprazolam by 32% citalopram had no effect. These findings are consistent with previous reports that fluoxetine and its active metabolite, norfluoxetine, produce moderate inhibition of CYP3A4 while citalopram does not. 

The single and multiple-dose pharmacokinetics of citalopram are linear and dose-proportional in the range 10-60 mg/day. Citalopram is metabolized to demethylcitalo-pram, didemethylcitalopram, citalopram-N-oxide, and a deaminated propionic acid derivative. Citalopram has a mean half-life of about 35 hours (4). Racemic citalopram is several times more potent than its metabolites in inhibiting serotonin reuptake (5). 

This suggests that even modest overdoses of citalopram can cause QTC prolongation and that cardiac monitoring should be considered. Based on the pharmacokinetic profile of citalopram and the temporal pattern of QTC change, the authors suggested that the effect of citalopram on the QTC interval was mediated by one of its metabolites, dimethylcitalopram. 

Citalopram 40 mg/day for 4 weeks did not alter the pharmacokinetics of digoxin 1 mg orally (34). Digoxin is not a CYP substrate, so an interaction with SSRIs is unlikely, but the authors cited a report that fluoxetine increased plasma digoxin concentrations (35). 

Larsen F, Priskorn M, Overo KF. Lack of citalopram effect on oral digoxin pharmacokinetics. J Clin Pharmacol 2001 41(3) 340-6. 

Propotnik M, Waschgler R, Konig P, Moll W, Conca A. Therapeutic drug monitoring of trazodone are there pharmacokinetic interactions involving citalopram and fluoxetine Int J Clin Pharmacol Ther 2004 42 120-4. 

A within-subject, double-bhnd, placebo-controlled, parallel design has been used to measure the effects of citalo-pram (20 mg/day) and fluoxetine (20 mg/day) on the pharmacokinetics and pharmacodynamics of alprazolam (1 mg/day) (45). Fluoxetine significantly impaired the metabolism of a single oral dose of alprazolam 1 mg, leading to prolongation of the half-life and an increased AUC, whereas citalopram did not. Neither SSRI significantly affected the pharmacodynamic effects of alprazolam. This experiment suggests differential effects of citalopram and fluoxetine on alprazolam kinetics. 

The effect of ketoconazole on the pharmacokinetics of citalopram has been studied in a double-blind, three-way, crossover trial in 18 men and women (38). The subjects received three treatments with a 14-day washout period a single dose of ketoconazole 200 mg plus placebo, a single dose of citalopram 40 mg plus placebo, and a single dose of ketoconazole 200 mg plus a single dose of citalopram 40 mg. There were no changes in the pharmacokinetics of citalopram after co-admimstration of ketoconazole, suggesting that ketoconazole and other CYP3A4 inhibitors can be safely co-administered with citalopram. 

Gutierrez M, Abramowitz W. Lack of effect of a single dose of ketoconazole on the pharmacokinetics of citalopram. Pharmacotherapy 2001 21(2) 163-8. 

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