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Review of pharmacokinetic and pharmacodynamic interaction studies with citalopram
European Neuropsychopharmacology 11 (2001) 275–283 www.elsevier.com / locate / euroneuro
Review
Review of pharmacokinetic and pharmacodynamic interaction studies with citalopram a, b Kim Brøsen *, Claudio A. Naranjo a
Institute of Public Health, Clinical Pharmacology, University of Southern Denmark, Winslowparken 19 DK-5000 Odense, Denmark b University of Toronto, Departments of Pharmacology, Psychiatry and Medicine and Psychopharmacology Research Program, Sunnybrook and Women’ s College Health Sciences Centre, Toronto, Canada Received 26 February 2001; accepted 12 June 2001
Abstract Citalopram is a selective serotonin reuptake inhibitor that is N-demethylated to N-desmethylcitalopram partially by CYP2C19 and partially by CYP3A4 and N-desmethylcitalopram is further N-demethylated by CYP2D6 to the likewise inactive metabolite didesmethylcitalopram. The two metabolites are not active. The fact that citalopram is metabolised by more than one CYP means that inhibition of its biotransformation by other drugs is less likely. Besides citalopram has a wide margin of safety, so even if there was a considerable change in serum concentration then this would most likely not be of clinical importance. In vitro citalopram does not inhibit CYP or does so only very moderately. A number of studies in healthy subjects and patients have confirmed, that this also holds true in vivo. Thus no change in pharmacokinetics or only very small changes were observed when citalopram was given with CYP1A2 substrates (clozapine and therophylline), CYP2C9 (warfarin), CYP2C19 (imipramine and mephenytoin), CYP2D6 (sparteine, imipramine and amitriptyline) and CYP3A4 (carbamazepine and triazolam). At the pharmacodynamic level there have been a few documented cases of serotonin syndrome with citalopram and moclobemide and buspirone. It is concluded that citalopram is neither the source nor the cause of clinically important drug–drug interactions. 2001 Elsevier Science B.V. All rights reserved. Keywords: Citalopram; SSRI; Interaction; CYP
1. Introduction A drug–drug interaction may be defined as an unwanted change in the action of a drug due to the previous or concomitant intake of another drug. The mechanism of an interaction either is pharmacodynamic, that is a change in the sensitivity for a drug at its site of action due to the presence of another drug or active principle, or it may be pharmacokinetic, that is altering the concentration of a drug or an active principle at its site of action with no change in the dose due to the previous or concomitant intake of another drug. The pharmacokinetic interactions may be subdivided into those involving drug absorption, drug elimination (excretion or biotransformation), drug distribution or local tissue metabolism. Many drugs are *Corresponding author. Tel.: 145-65-503-751; fax: 145-65-916-089. E-mail address: [email protected] (K. Brøsen).
protein bound in plasma, and it is only the unbound fraction that is pharmacologically active. Thus displacement may take place if the patient concomitantly is treated with another drug bound to the same plasma protein (albumin, orosomucoid and others). This type of drug– drug interaction was previously thought to be very important, because it gives rise to an increase in the unbound fraction and hence it increases the pharmacological response. However, it should be borne in mind, that the unbound fraction is eliminated more easily. Accordingly a new equilibrium is quickly established where the concentration of the unbound drug is the same as before the displacement. Hence, interactions taking place at the protein binding level in practice are without any clinical importance. This review deals with pharmacokinetic interactions involving citalopram, i.e. interactions where either the (plasma)-tissue concentration of citalopram is altered or
0924-977X / 01 / $ – see front matter 2001 Elsevier Science B.V. All rights reserved. PII: S0924-977X( 01 )00101-8
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interactions where potentially the (plasma)-tissue concentration of another drug or active moiety is changed due to the concomitant intake of citalopram. Purely pharmacodynamic interactions are also dealt with. The molecular mechanisms of drug absorption and of biotransformation via the cytochrome P450 enzyme system is first dealt with in some more detail.
neither inhibit nor induce leave the digoxin concentrations unchanged (Greiner et al., 1999). There are recent in vitro data suggesting that citalopram gets across the blood–brain barrier by means of a nonstereoselective symmetrical carrier-mediated mechanism serving both as an influx and an efflux transporter. There was no evidence supporting a role of P-glycoprotein for the transport of citalopram across the brain vessels (Rochat et al., 1999)
2. Drug absorption and P-glycoprotein Oral intake is by far the most common route of administration of drugs. Absorption via the gut mucosa is necessary for the drug to reach the systemic circulation. This requires that the drug can be dissolved in the fluids of the gastrointestinal tract, that it is chemically stable and that it can get across the gut wall by passive diffusion. The latter means that the drug should be a lipophilic and not too large molecule. These are the same characteristics that make it possible for the drug to get from plasma to the tissues. P-Glycoprotein is an integral cell membrane protein which serves as an ATP-dependent efflux pump (Silverman, 1999; Fromm, 2000). The initial interest in Pglycoprotein was due to its role in multidrug resistance in tumor cells. Cancer chemotherapeutic agents are actively secreted out of tumor cells expressing P-glycoprotein, thus making the cancer resistant to treatment. More recently it has been shown that P-glycoprotein is also expressed under physiological conditions in normal tissue. It is strategically located in the apical domain of enterocytes, bile epithelial cells and in the renal proximal tubules, where it causes diminished absorption from the gut, increased secretion with the bile and increased renal excretion. Thus Pglycoprotein is a protective protein causing reduced plasma concentrations for drugs that are substrates including digoxin, quinidine, etoposide, vinblastine, paclitaxel, cyclosporine, HIV-1 protease inhibitors and many other drugs. Moreover, P-glycoprotein is expressed in the luminal part of the endothelial cells of the brain capillaries, and this diminishes the CNS penetration of substrates. Drugs that induce, that is increase, the expression of P-glycoprotein such as rifampicin (Greiner et al., 1999) enhance the effect, whereas the reverse is the case with drugs that inhibit P-glycoprotein causing elevated plasma concentration through increased bioavailability and lowered secretion in the bile and urine. Thus the elucidation of the pharmacokinetic role of P-glycoprotein has provided new insights in the mechanisms of certain drug–drug interactions such as the well-known interaction between digoxin and quinidine. There is evidence supporting that the plasma levels of digoxin following oral dosing may serve as a biomarker for the intestinal expression of P-glycoprotein. Drugs that inhibit P-glycoprotein cause increased plasma concentrations of digoxin, drugs that induce Pglycoprotein lower the plasma concentration and drugs that
3. Cytochrome P450 Approximately 50 different cytochrome P450 (CYPs) enzymes have been identified in humans; they are haem proteins with a single protein chain and haem as the prosthetic group. The enzymes and their corresponding genes are classified into families and subfamilies according to the degree of amino acid similarity of the gene products. Thus CYPs with less than about 40% of amino acid similarity belong to different families numbered consecutively with Arabic numerals 1,2,3,4, etc. Within families enzymes with more than 40% but less than 55% amino acid similarity belong to different subfamilies characterized with capital letters A,B,C,D, etc. Finally in the individual subfamily there may be different enzymes with more than 55% but less than 99% amino acid similarity and they too are numbered consecutively with Arabic numerals. In humans there are 8–10 important dug metabolizing CYPs and they have different but overlapping substrate specificities. The drug oxidizing CYPs are located in membranes of the smooth endoplasmic reticulum primarily in hepatocytes but also in gut mucosa, kidneys, lung tissue, skin, and in the brain. Their role is to oxidize numerous drugs and other foreign chemicals. Interand intra-individual differences in the expression and function of CYPs still is considered a major source for variability in plasma and hence also tissue concentrations. This also applies to drug–drug interactions that may occur if two drugs that are substrates for the same CYP are coadministered, especially if one of the drugs is primarily eliminated by a single CYP, if the other drug is a potent or an effective inhibitor of the particular CYP, if the therapeutic plasma concentration range is narrow and if clinical dose titration is not feasible. The most important CYPs are CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4. Some of their major characteristics are summarized in Fig. 1 and detailed below. CYP1A2 is one of the major CYPs accounting for about 15% of the total cytochrome P450 in the human liver (Shimada et al., 1994). It is highly inducible by tobacco smoke, polyaromatic hydrocarbons, omeprazole and components in cruciferous vegetables and it is inhibited by oral contraceptives. It is the major CYP involved in the biotransformation of several psychotropic drugs including tacrine, clozapine, olanzapine but also in the biotrans-
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Fig. 1. Major drug metabolizing cytochrome P450 enzymes (CYPs).
formation of the methylxanthines caffeine and theophylline (Fig. 1). Fluvoxamine is a very potent inhibitor of CYP1A2 (Brøsen et al., 1993) and the plasma levels of most CYP1A2 substrates should be monitored carefully during fluvoxamine intake. The activity of CYP1A2 in vivo can be monitored by assessment of caffeine metabolism, but in clinical practice this measurement does not play a role (Larsen et al., 1999). CYP2C9 oxidizes most non-steroidal antiinflammatory drugs but also fluvastatin, tolbutamid, phenytoin and S-warfarin. In fact most of the pharmacokinetic interactions between warfarin and other drugs are due either to induction or inhibition of CYP2C9. Two so-called single nucleotide polymorphisms (SNPs) in the CYP2C9 gene, CYP2 C9*2, which makes cysteine replace arginine at amino acid position 144 and CYP2 C9*3 which causes a shift from isoleucine to leucine at position 359 in the enzyme CYP2C9 (Aithal et al., 1999). These amino acid changes result in a dramatic lowering of CYP2C9 activity and hence very slow metabolism of CYP2C9 substrates. CYP2C19 is the source of the Smephenytoin oxidation polymorphism. It has been established that about 2% of whites and 20% of Orientals are poor metabolizers and they do not possess the enzyme because they inherited a SNP in exon 5 and more rarely a
SNP in exon 4 of the CYP2 C19 gene from their parents (Rettie et al., 2000). CYP2C19 is partly involved in the oxidation of citalopram, imipramine, clomipramine, moclobemide, diazepam, omeprazole and proguanil. Fluoxetine and fluvoxamine inhibit this enzyme very effectively (Jeppesen et al., 1994). CYP2D6 is the source of the sparteine / debrisoquine oxidation polymorphism, and several mutations and other changes in DNA cause the absence of the enzyme from the livers of about 7% of whites and 1–2% of Blacks and Orientals, the so-called poor metabolizers. CYP2D6 is the major enzyme catalysing the biotransformation of tricyclic antidepressants, several selective serotonin reuptake inhibitors (especially fluoxetine and paroxetine), some antipsychotics, antiarrhythmics, b-adrenoceptor blockers and opiates (Fig. 1). There are several potent inhibitors of CYP2D6 including antiarrhythmics (quinidine, flecainide, propafenone), antipsychotics (levomepromazine, perfenazine, thioridazine) and SSRIs (paroxetine and fluoxetine) (Brøsen and Gram, 1989; Brøsen, 1993). CYP3A4 makes up more than 30% of the total P450 in the human liver (Shimada et al., 1994), making it the most abundant CYP not only in the liver but also in the gut mucosa. Accordingly, CYP3A4 by far is the most important drug metabolising CYP and it oxidizes
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carbamazepine, midazolam and triazolam, nefazodone, cyclosporine, calcium antagonists, quinidine, lipid-lowering drugs, HIV-1 protease inhibitors (Wrighton and Thummel, 2000). It is an inducible enzyme, and clinically the most important inducers are carbamazepine and rifampicin. It is the source of numerous clinically important drug–drug interactions especially including substrates that are potent or effective inhibitors such as erythromycin, ketoconazole, nefazodone, norfluoxetine (active metabolite of fluoxetine) and the HIV-1 protease inhibitors.
4. Pharmacokinetics and drug serum concentrations and clinical response of citalopram Citalopram is administered as a racemic mixture and the inhibition of serotonin reuptake is associated almost exclusively by the S-enantiomer (Hyttel et al., 1992). Citalopram is N-demethylated to N-desmethylcitalopram partially by CYP2C19 and CYP3A4 (Gram et al., 1993; Sindrup et al., 1993; Kobayashi et al., 1997; Rochat et al., 1997; von Moltke et al., 1999; Olesen and Linnet, 1999) and desmethylcitalopram is further N-demethylated by CYP2D6 (Sindrup et al., 1993). The two metabolites do not contribute to the antidepressant effect. Citalopram is completely absorbed from the intestine (Kragh-Sørensen et al., 1981). The total clearance following oral intake is about 26 l / h in extensive metabolizers with regard to CYP2C19 and about half this value in poor metabolizers (Sindrup et al., 1993) the volume of distribution is about 14 l / kg and the elimination half-life for the active compound is 33 h (Kragh-Sørensen et al., 1981; Sindrup et al., 1993) and somewhat longer in poor metabolizers. At recommended clinical doses of citalopram between 20 and 60 mg / day, plasma levels of racemic citalopram and desmethylcitalopram range from 9 to 200 ng / ml and 10 to 105 ng / ml, respectively (summarized by Buur Rasmussen and Brøsen, 2000). In the dose range from 10 to 60 mg / day, citalopram and its two demethylated metabolites displayed linear pharmacokinetics (Baumannn and Larsen, 1995). When using a stereoselective method, concentration ranges of S-citalopram: 9–106 ng / ml, Rcitalopram: 20–186 ng / ml, S-desmethylcitalopram: 4–38 ng / ml and R-desmethylcitalopram: 3–75 ng / ml were observed (Rochat et al., 1995). Thus the mean ratio between S- and R-citalopram was 0.56 with a range of 0.32–0.97, and this was later confirmed (Sidhu et al., 1997). This suggests a more rapid elimination of the active S-enantiomer compared with the inactive R-enantiomer, and recent in vitro studies support this (Rochat et al., 1997). Numerous studies have been conducted aiming at establishing a correlation between citalopram serum concentration and effect in the treatment of depression (Baumann, 1996). Thus there is no evidence for a therapeutic window or a concentration threshold above which there is an increased risk for adverse effects (Dufour et al., 1987; Baumannn et al., 1996; Bjerkenstedt et al., 1985).
However, one case report on a severely depressed woman showed that showed that a dose of 20 mg / day had higher efficacy than a dose of 40 mg / day, suggesting that after all there may be a kind of a therapeutic window (Benazzi, 1996).
5. SSRIs and pharmacokinetic interactions The drug discovery and development process for citalopram and other SSRIs started in the early 1970s, and during that time no one thought of investigating their relationship with cytochrome P450. Thus once the SSRIs were approved for marketing in the late 1980s virtually nothing was known about which CYPs that catalyse their biotransformation, nor which CYPs they are influencing by SSRI administration. It came as a big surprise when case reports showed interactions between fluoxetine and CYP2D6 substrates such as desipramine and nortriptyline (Vaughan, 1988), and paroxetine and the model drug sparteine (Brøsen et al., 1991). In essence, extensive metabolizers of the CYP2D6 type changed phenotype to poor metabolizers during fluoxetine and paroxetine intake, suggesting that the two SSRIs are potent inhibitors of CYP2D6. The very early clinical observations prompted both in vitro and in vivo investigations on this matter. The early studies (Brøsen and Skjelbo, 1991; Skjelbo and Brøsen, 1992; Crewe et al., 1992) confirmed that fluoxetine, its active metabolite norfluoxetine and paroxetine are potent inhibitors of CYP2D6 and that citalopram, fluvoxamine and sertraline are weak to moderate inhibitors unlikely to cause clinically important interactions with substrates of this enzyme. A very recent study showed, that S-citalopram (Greenblatt et al., 2000) as expected also is a very weak inhibitor of CYP2D6 in vitro. The studies were subsequently extended to include also other CYPs, and we now have a very good picture of the relationship between CYP and SSRIs. Thus to summarize, fluvoxamine is a potent inhibitor of both CYP1A2 and CYP2C19 and a moderate inhibitor of CYP2C9 (Madsen et al., 2001) fluoxetine, norfluoxetine and paroxetine are potent inhibitors of CYP2D6 and norfluoxetine is a moderate inhibitor of CYP3A4 (Table 1). The original work on which this ultrashort account is based is cited in a number of comprehensive reviews written by some of the active researchers in the field (Brøsen, 1993, 1998; Brøsen and Rasmussen, 1996; Baumannn, 1996; Greenblatt et al., 1998, 1999). Below there is a more detailed account on the more recent work and observations regarding citalopram.
6. Potential pharmacokinetic interactions with citalopram caused by other drugs The fact that citalopram is metabolised by more than one CYP, notably CYP2C19 and CYP3A4, means that inhibition of its biotransformation by other drugs is less
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Table 1 Relative inhibitory potency of the SSRIs with respect to four of the most important CYPs SSRI
CYP 2D6 b KI (mmol / l) Dextromethorphan probe
CYP 3Ab KI (mmol / l) Alprazolam probe
CYP 2C19 b KI (mmol / l) S-Mephenytoin probe
CYP 1A2 IC 50 c (mM) Paracetamol probe
Citalopram Desmethyl-citalopram Fluoxetine Norfluoxetine Fluvoxamine Paroxetine Sertraline
7 6 0.17 0.19 1.8 0.065 1.5
a
87.3 55.8 5.2 1.1
.100 .100 .100 .100 0.2 45 70
a
83.3 11.1 10.2 39.4 23.8
]
7.5 2.0
Adapted with permission from Naranjo et al. (1999). a Minimal or no inhibition. b KI , inhibitor constant. c IC 50 , the concentration of the inhibitor which reduced the formation of a metabolite by 50% where lower values indicate higher inhibitory potency.
likely. Besides citalopram has a wide margin of safety, and even if there was a change in the plasma levels of citalopram caused by the concomitant intake of other drugs this would be unlikely to cause clinical complications. In the literature there is one possible exception. In two patients, a substitution of the CYP inducing agent carbamazepine with the much less inducing oxcarbazepine resulted in a threefold and eightfold increase in citalopram levels, which in one of the patients caused increased anxiety and tremor (Leinonen et al., 1996a). Daily intake of 800 mg of cimetidine, a well-known universal CYP inhibitor, resulted in an average increase in the steady-state plasma concentration of citalopram of 41% in 12 healthy subjects (Priskorn et al., 1997a). Leinonen reported moderate increases (about 20%) in citalopram steady-state concentrations in patients taking various antipsychotics and benzodiazepines (Leinonen et al., 1996b). However, this was not a controlled study; patients were taking varied doses of all medications and there were no before and after serum levels, which makes it difficult to control for the large interindividual variation observed in serum citalopram concentrations. Comedication with a single oral dose of 50 mg of the potent CYP2D6 inhibitor levomepromazine (Gram et al., 1993) did not change the serum concentration of citalopram, but increased the level of desmethylcitalopram, consistent with this metabolite being further metabolized by CYP2D6. Concomitant intake of tricyclic antidepressants resulted in a 44% increase in citalopram levels. The most pronounced effect among the tricyclic antidepressants was seen with clomipramine (Leinonen et al., 1996b; Lepola et al., 1994), and this is consistent with this drug being a relatively potent inhibitor of both CYP2C19 and CYP2D6 (Nielsen et al., 1992). In seven depressed women (Bondolfi et al., 1996) who took citalopram 40 mg / day there was an increase in the average plasma levels of S-citalopram from 27 to 83 ng / ml and of R-citalopram from 55 to 98 ng / ml during concomitant intake of fluvoxamine 50 mg / day. Accordingly the S: R ratio increased from an average of 0.48 to 0.84, suggesting, that the CYPs involved in metabolism of S-citalopram are more affected by fluvoxamine than those involved in the oxidation of R-citalopram. The same applies to fluoxetine,
where a clinical study of 11 patients taking citalopram 40 mg / day experienced a doubling of their S-citalopram steady-state concentration and a 50% increase of their R-citalopram levels during concomitant intake of fluoxetine 10 mg / day (Bondolfi et al., 2000). The interactions are most certainly due to fluvoxamine and fluoxetine both being potent inhibitors of CYP2C19 in vivo (Jeppesen et al., 1996). Co-administration of a single oral dose of ketoconazole, a well-known CYP3A4 inhibitor, did not result in a statistically significant change in the pharmacokinetics of a single oral dose of 40 mg citalopram (Gutierrez and Abramowitz, 2001).
7. Potential interactions caused by citalopram As mentioned earlier, citalopram does not inhibit CYP or it does so only very moderately in vitro. A number of studies with healthy subjects or patients have recently been performed to verify that this holds true also in vivo: CYP1A2 (clozapine and theophylline), CYP2C9 (warfarin), CYP2C19 (imipramine and mephenytoin), CYP2D6 (sparteine, imipramine and amitriptyline), CYP3A4 (carbamazepine and triazolam) and CYP2C9 (warfarin).
7.1. Tricyclic antidepressants There has been one case report which noted increased serum drug concentrations of clomipramine, alprazolam and citalopram only after citalopram was added to the two other drugs, possibly due to inhibition of CYP2D6, which is largely responsible for the metabolism of clomipramine, and CYP 3A4, which metabolizes alprazolam (Lepola et al., 1994). A 53-year-old woman committed suicide by taking an overdose of trimipramine (Musshoff et al., 1999), but the role of concomitant intake of citalopram was not clear. One study by Gram et al. (1993) showed that citalopram caused a 50% increase in the single-dose area under the serum concentration–time curve of the desipramine metabolite of imipramine in 8 healthy male volunteers after 40 mg / day citalopram for 10 days. The increase in the parent
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drug concentration did not reach a level of statistical significance (Gram et al., 1993), and this is partially explained by the fact, that citalopram despite being a substrate for CYP2C19 does not inhibit the enzyme at clinically relevant doses (Jeppesen et al., 1996). Clinically, however, one case study involving a patient who was experiencing ataxia, confusion and lightheadedness secondary to supratherapeutic levels of desipramine after paroxetine augmentation, demonstrated reduced desipramine levels and toxicity after switching to citalopram (Ashton, 2000). Desipramine toxicity was likely caused by CYP2D6 inhibition by paroxetine, indicating that this blockade might be minimized with use of citalopram. Citalopram appeared to have no effect on amitriptyline and nortriptyline plasma concentrations in five case studies (Baettig et al., 1993). Somewhat surprisingly a near doubling of N-desmethyl clomipramine was reported in a patient who both took clomipramine, 75 mg / day and citalopram 40 mg / day (Haffen et al., 1999). This could be due to a relatively low CYP2D6 content because the patient was a heterozygous carrier of the nonfunctional CYP2D6*6.
7.2. Serotonin syndrome Serotonin syndrome is a rare but serious event that can occur when medications that act to increase serotonin at the synaptic junction are coadministered (Sternbach, 1991). Serotonin syndrome is characterized by a constellation of symptoms that include mental status changes, agitation, myoclonus, hyperreflexia, sweating, shivering, tremor, diarrhea, lack of coordination, and fever. There have been a few documented cases of serotonin syndrome with citalopram and moclobemide (Neuvonen et al., 1994; Guma et al., 1999), and one case after a citalopram– buspirone combination (Spigset and Adielsson, 1997). However, there is little information available about the comparative risk among the different SSRIs.
7.3. SSRIs There are no published in vivo examples of interactions between citalopram and other SSRIs.
7.4. Benzodiazepines Depression and anxiety are highly comorbid. Data from Maier and Falkai (1999) in a primary care setting found that the observed rate of comorbidity between anxiety and depression was almost five times higher than the expected rate of comorbidity as determined by the World Health Organization. Therefore, we would expect there to be a significant number of patients receiving combination pharmacotherapy for both disorders. There have been no case reports of the effects of citalopram on the pharmacokinetics of benzodiazepines. A recent controlled,
within-subjects study by Nolting compared acute-dose pharmacokinetics of triazolam 0.25 mg before and after 4 weeks of citalopram administration (20 mg / day in week 1; 40 mg / day for 3 weeks) and found no change in plasma triazolam AUC before and after citalopram, possibly indicating little inhibition of the CYP 3A4 enzyme (Nolting and Abramowitz, 2000). In a similar randomized placebo-controlled within-subjects study, citalopram did not cause any changes in the plasma AUC of alprazolam (n510), unlike fluoxetine, which caused a significant increase in the AUC of alprazolam (n511) [C.A. Naranjo, personal communication].
7.5. Antiepileptics /mood stabilizers Citalopram appears not to interact with carbamazepine in vivo. One study found no change in 35 days dosing (400 mg) carbamazepine pharmacokinetics before and after administration of citalopram 40 mg / day for 14 days (Møller et al., 2000a).
7.6. Antipsychotics Approximately 25% of schizophrenic patients have intervals of major depression during the course of their illness, making the issue of comedication with antidepressants of major importance. A randomized, placebo-controlled parallel study was carried out in 90 stabilized schizophrenic patients. Citalopram 40 mg / day was given as augmentation therapy with previously prescribed antipsychotics. No major alterations in plasma antipsychotic levels were discovered in any medication; haloperidol, chlorpromazine, zuclopenthixol, levomepromazine, ¨ thioridazine, and perphenazine (Syvalahti et al., 1997). In a non-randomized, open trial in five in-patients stabilized on clozapine, Taylor et al. (1998) found no change in clozapine concentrations after augmentation with 20 mg / day citalopram. However, a recent case report suggested otherwise. A schizophrenic man experienced sedation, new-onset fatigue, confusion, enuresis and hypersalivation secondary to supratherapeutic levels of clozapine after augmentation with 40 mg / day of citalopram (Borba and Henderson, 2000). Symptoms disappeared and clozapine levels dropped significantly after reduction of citalopram to 20 mg / day, suggestive of possible CYP1A2 or 3A4 blockade at the higher dose of citalopram. Avenoso, however, found no change in clozapine or risperidone serum levels after citalopram 40 mg / day augmentation in 15 schizophrenics stabilized on clozapine or risperidone for at least 6 months (Avenoso et al., 1998).
7.7. Lithium Citalopram does not appear to alter the kinetics of lithium when the two are coadministered (Gram et al., 1993), however a study by Baumannn et al. (1996)
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suggested that lithium augmentation in depression was an effective treatment in non-responders to citalopram alone.
7.8. Other non-CNS drugs Citalopram did not change the pharmacokinetics of theophylline, a CYP1A2 substrate (Møller et al., 2000b).
7.9. Drugs used in the elderly At least 4% of elderly patients living in the community suffer from a major depressive disorder and some 15% from less severe forms of depressive illness. Furthermore, psychiatric and physical comorbidity is high in the aged and the incidence of depression may reach 40–50% in common medical disorders such as diabetes and cardiac insufficiency (Strnad and Bahro, 1999). It is important to know how drugs commonly used in the elderly will interact with antidepressant medications. A study in 18 healthy nonsmoking white men (ages 19–28) compared the pharmacokinetics of both acute dose and chronic (4-day) administration of selegiline (10 mg / day) after 10–14 days of citalopram 20 mg / day (Laine et al., 1997). Neither serum citalopram nor serum selegiline appeared to be affected by the other. Another recent study (Larsen et al., 2001) compared the renal clearance of acute digoxin before and after chronic citalopram 40 mg / day in thirteen healthy male and female volunteers (18–40 years old). Volunteers deficient in CYP2D6 and CYP2C19, as determined by metabolic phenotyping for poor metabolizers of sparteine and mephenytoin, were excluded. Citalopram did not have any significant effect on serum levels of digoxin, and this speaks against citalopram being an inhibitor of P-glycoprotein. In keeping with this, the mean plasma concentrations of another P-glycoprotein and CYP3A4 substrate, cyclosporine (Lown et al., 1997) at baseline in five patients treated with doses ranging from 75 to 225 mg twice daily was |220 and |210 ng / ml during citalopram 10–20 mg / day (Liston et al., 2000). An open, randomized, crossover study in healthy males compared the acute dose pharmacokinetics of warfarin before and after 21 days of citalopram (40 mg / day) in 12 healthy males (21–32 years old). Citalopram produced no changes in the pharmacokinetics of (R)- and (S)-warfarin, indicating no drug interactions via CYP1A2, CYP3A4 or CYP2C9 (Priskorn et al., 1997b). Citalopram produced a statistically significant increase in the maximum prothrombin time and the area under the prothrombin time–time curve, however this increase is not considered to be important in the clinical setting (Priskorn et al., 1997b).
7.10. Drugs of abuse There have been no case reports or controlled studies investigating the pharmacokinetic interaction between citalopram and alcohol. However, citalopram has been
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used in several studies as an adjunct in the treatment of alcohol dependence, where it seems to have clinical efficacy, and there appears to be no evidence for acute kinetic or dynamic interactions between alcohol and citalopram (Lader et al., 1986; Gorelick, 1989). Lack of potentiation of alcohol effects has been noted consistently in these studies. Interestingly, a placebo-controlled, randomized study found that pretreatment with citalopram was able to attenuate the psychological state produced by an acute dose of 3,4-methylenedioxymethamphetamine (MDMA) in 16 healthy volunteers (Liechti et al., 2000). MDMA is a recreational drug that produces heightened mood, increased self-confidence and extroversion. MDMA has been shown to release serotonin and dopamine in animal brains, suggesting a possible mechanism of action. Since citalopram acts by inhibiting serotonin reuptake, this is an example of a pharmacodynamic interaction between citalopram and another psychotropic medication. In a crossover study, eight healthy subjects (von Bahr et al., 2000) took either citalopram, 40 mg, fluvoxamine, 50 mg, or placebo on three separate occasions as single oral doses. The serum concentration of melatonin was determined at regular intervals for up 20 h following drug or placebo intake. Thus after fluvoxamine the area under the plasma concentration versus time curve increased nearly three times for melatonin compared with placebo whereas there was no statistically significant change following citalopram. The study suggests that fluvoxamine but not citalopram inhibits the CYP, possibly CYP1A2 and CYP2C19, responsible for the breakdown of melatonin.
8. Conclusion In conclusion, citalopram is neither the source nor the cause of any clinically important pharmacokinetic drug– drug interactions. Other SSRIs, paroxetine, fluoxetine, and fluvoxamine, display greater in vitro inhibition of CYP3A4, CYP2D6, CYP2C19 and CYP1A2 than citalopram, and this is also reflected in their drug interaction profiles (Sproule et al., 1997). This suggests that citalopram may be a better choice than the other SSRIs in patients who are at high risk of experiencing metabolic drug interactions, for example patients on multidrug therapy, particularly elderly patients who may be more sensitive to small elevations in drug concentrations.
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Review
Review of pharmacokinetic and pharmacodynamic interaction studies with citalopram a, b Kim Brøsen *, Claudio A. Naranjo a
Institute of Public Health, Clinical Pharmacology, University of Southern Denmark, Winslowparken 19 DK-5000 Odense, Denmark b University of Toronto, Departments of Pharmacology, Psychiatry and Medicine and Psychopharmacology Research Program, Sunnybrook and Women’ s College Health Sciences Centre, Toronto, Canada Received 26 February 2001; accepted 12 June 2001
Abstract Citalopram is a selective serotonin reuptake inhibitor that is N-demethylated to N-desmethylcitalopram partially by CYP2C19 and partially by CYP3A4 and N-desmethylcitalopram is further N-demethylated by CYP2D6 to the likewise inactive metabolite didesmethylcitalopram. The two metabolites are not active. The fact that citalopram is metabolised by more than one CYP means that inhibition of its biotransformation by other drugs is less likely. Besides citalopram has a wide margin of safety, so even if there was a considerable change in serum concentration then this would most likely not be of clinical importance. In vitro citalopram does not inhibit CYP or does so only very moderately. A number of studies in healthy subjects and patients have confirmed, that this also holds true in vivo. Thus no change in pharmacokinetics or only very small changes were observed when citalopram was given with CYP1A2 substrates (clozapine and therophylline), CYP2C9 (warfarin), CYP2C19 (imipramine and mephenytoin), CYP2D6 (sparteine, imipramine and amitriptyline) and CYP3A4 (carbamazepine and triazolam). At the pharmacodynamic level there have been a few documented cases of serotonin syndrome with citalopram and moclobemide and buspirone. It is concluded that citalopram is neither the source nor the cause of clinically important drug–drug interactions. 2001 Elsevier Science B.V. All rights reserved. Keywords: Citalopram; SSRI; Interaction; CYP
1. Introduction A drug–drug interaction may be defined as an unwanted change in the action of a drug due to the previous or concomitant intake of another drug. The mechanism of an interaction either is pharmacodynamic, that is a change in the sensitivity for a drug at its site of action due to the presence of another drug or active principle, or it may be pharmacokinetic, that is altering the concentration of a drug or an active principle at its site of action with no change in the dose due to the previous or concomitant intake of another drug. The pharmacokinetic interactions may be subdivided into those involving drug absorption, drug elimination (excretion or biotransformation), drug distribution or local tissue metabolism. Many drugs are *Corresponding author. Tel.: 145-65-503-751; fax: 145-65-916-089. E-mail address: [email protected] (K. Brøsen).
protein bound in plasma, and it is only the unbound fraction that is pharmacologically active. Thus displacement may take place if the patient concomitantly is treated with another drug bound to the same plasma protein (albumin, orosomucoid and others). This type of drug– drug interaction was previously thought to be very important, because it gives rise to an increase in the unbound fraction and hence it increases the pharmacological response. However, it should be borne in mind, that the unbound fraction is eliminated more easily. Accordingly a new equilibrium is quickly established where the concentration of the unbound drug is the same as before the displacement. Hence, interactions taking place at the protein binding level in practice are without any clinical importance. This review deals with pharmacokinetic interactions involving citalopram, i.e. interactions where either the (plasma)-tissue concentration of citalopram is altered or
0924-977X / 01 / $ – see front matter 2001 Elsevier Science B.V. All rights reserved. PII: S0924-977X( 01 )00101-8
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interactions where potentially the (plasma)-tissue concentration of another drug or active moiety is changed due to the concomitant intake of citalopram. Purely pharmacodynamic interactions are also dealt with. The molecular mechanisms of drug absorption and of biotransformation via the cytochrome P450 enzyme system is first dealt with in some more detail.
neither inhibit nor induce leave the digoxin concentrations unchanged (Greiner et al., 1999). There are recent in vitro data suggesting that citalopram gets across the blood–brain barrier by means of a nonstereoselective symmetrical carrier-mediated mechanism serving both as an influx and an efflux transporter. There was no evidence supporting a role of P-glycoprotein for the transport of citalopram across the brain vessels (Rochat et al., 1999)
2. Drug absorption and P-glycoprotein Oral intake is by far the most common route of administration of drugs. Absorption via the gut mucosa is necessary for the drug to reach the systemic circulation. This requires that the drug can be dissolved in the fluids of the gastrointestinal tract, that it is chemically stable and that it can get across the gut wall by passive diffusion. The latter means that the drug should be a lipophilic and not too large molecule. These are the same characteristics that make it possible for the drug to get from plasma to the tissues. P-Glycoprotein is an integral cell membrane protein which serves as an ATP-dependent efflux pump (Silverman, 1999; Fromm, 2000). The initial interest in Pglycoprotein was due to its role in multidrug resistance in tumor cells. Cancer chemotherapeutic agents are actively secreted out of tumor cells expressing P-glycoprotein, thus making the cancer resistant to treatment. More recently it has been shown that P-glycoprotein is also expressed under physiological conditions in normal tissue. It is strategically located in the apical domain of enterocytes, bile epithelial cells and in the renal proximal tubules, where it causes diminished absorption from the gut, increased secretion with the bile and increased renal excretion. Thus Pglycoprotein is a protective protein causing reduced plasma concentrations for drugs that are substrates including digoxin, quinidine, etoposide, vinblastine, paclitaxel, cyclosporine, HIV-1 protease inhibitors and many other drugs. Moreover, P-glycoprotein is expressed in the luminal part of the endothelial cells of the brain capillaries, and this diminishes the CNS penetration of substrates. Drugs that induce, that is increase, the expression of P-glycoprotein such as rifampicin (Greiner et al., 1999) enhance the effect, whereas the reverse is the case with drugs that inhibit P-glycoprotein causing elevated plasma concentration through increased bioavailability and lowered secretion in the bile and urine. Thus the elucidation of the pharmacokinetic role of P-glycoprotein has provided new insights in the mechanisms of certain drug–drug interactions such as the well-known interaction between digoxin and quinidine. There is evidence supporting that the plasma levels of digoxin following oral dosing may serve as a biomarker for the intestinal expression of P-glycoprotein. Drugs that inhibit P-glycoprotein cause increased plasma concentrations of digoxin, drugs that induce Pglycoprotein lower the plasma concentration and drugs that
3. Cytochrome P450 Approximately 50 different cytochrome P450 (CYPs) enzymes have been identified in humans; they are haem proteins with a single protein chain and haem as the prosthetic group. The enzymes and their corresponding genes are classified into families and subfamilies according to the degree of amino acid similarity of the gene products. Thus CYPs with less than about 40% of amino acid similarity belong to different families numbered consecutively with Arabic numerals 1,2,3,4, etc. Within families enzymes with more than 40% but less than 55% amino acid similarity belong to different subfamilies characterized with capital letters A,B,C,D, etc. Finally in the individual subfamily there may be different enzymes with more than 55% but less than 99% amino acid similarity and they too are numbered consecutively with Arabic numerals. In humans there are 8–10 important dug metabolizing CYPs and they have different but overlapping substrate specificities. The drug oxidizing CYPs are located in membranes of the smooth endoplasmic reticulum primarily in hepatocytes but also in gut mucosa, kidneys, lung tissue, skin, and in the brain. Their role is to oxidize numerous drugs and other foreign chemicals. Interand intra-individual differences in the expression and function of CYPs still is considered a major source for variability in plasma and hence also tissue concentrations. This also applies to drug–drug interactions that may occur if two drugs that are substrates for the same CYP are coadministered, especially if one of the drugs is primarily eliminated by a single CYP, if the other drug is a potent or an effective inhibitor of the particular CYP, if the therapeutic plasma concentration range is narrow and if clinical dose titration is not feasible. The most important CYPs are CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4. Some of their major characteristics are summarized in Fig. 1 and detailed below. CYP1A2 is one of the major CYPs accounting for about 15% of the total cytochrome P450 in the human liver (Shimada et al., 1994). It is highly inducible by tobacco smoke, polyaromatic hydrocarbons, omeprazole and components in cruciferous vegetables and it is inhibited by oral contraceptives. It is the major CYP involved in the biotransformation of several psychotropic drugs including tacrine, clozapine, olanzapine but also in the biotrans-
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Fig. 1. Major drug metabolizing cytochrome P450 enzymes (CYPs).
formation of the methylxanthines caffeine and theophylline (Fig. 1). Fluvoxamine is a very potent inhibitor of CYP1A2 (Brøsen et al., 1993) and the plasma levels of most CYP1A2 substrates should be monitored carefully during fluvoxamine intake. The activity of CYP1A2 in vivo can be monitored by assessment of caffeine metabolism, but in clinical practice this measurement does not play a role (Larsen et al., 1999). CYP2C9 oxidizes most non-steroidal antiinflammatory drugs but also fluvastatin, tolbutamid, phenytoin and S-warfarin. In fact most of the pharmacokinetic interactions between warfarin and other drugs are due either to induction or inhibition of CYP2C9. Two so-called single nucleotide polymorphisms (SNPs) in the CYP2C9 gene, CYP2 C9*2, which makes cysteine replace arginine at amino acid position 144 and CYP2 C9*3 which causes a shift from isoleucine to leucine at position 359 in the enzyme CYP2C9 (Aithal et al., 1999). These amino acid changes result in a dramatic lowering of CYP2C9 activity and hence very slow metabolism of CYP2C9 substrates. CYP2C19 is the source of the Smephenytoin oxidation polymorphism. It has been established that about 2% of whites and 20% of Orientals are poor metabolizers and they do not possess the enzyme because they inherited a SNP in exon 5 and more rarely a
SNP in exon 4 of the CYP2 C19 gene from their parents (Rettie et al., 2000). CYP2C19 is partly involved in the oxidation of citalopram, imipramine, clomipramine, moclobemide, diazepam, omeprazole and proguanil. Fluoxetine and fluvoxamine inhibit this enzyme very effectively (Jeppesen et al., 1994). CYP2D6 is the source of the sparteine / debrisoquine oxidation polymorphism, and several mutations and other changes in DNA cause the absence of the enzyme from the livers of about 7% of whites and 1–2% of Blacks and Orientals, the so-called poor metabolizers. CYP2D6 is the major enzyme catalysing the biotransformation of tricyclic antidepressants, several selective serotonin reuptake inhibitors (especially fluoxetine and paroxetine), some antipsychotics, antiarrhythmics, b-adrenoceptor blockers and opiates (Fig. 1). There are several potent inhibitors of CYP2D6 including antiarrhythmics (quinidine, flecainide, propafenone), antipsychotics (levomepromazine, perfenazine, thioridazine) and SSRIs (paroxetine and fluoxetine) (Brøsen and Gram, 1989; Brøsen, 1993). CYP3A4 makes up more than 30% of the total P450 in the human liver (Shimada et al., 1994), making it the most abundant CYP not only in the liver but also in the gut mucosa. Accordingly, CYP3A4 by far is the most important drug metabolising CYP and it oxidizes
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carbamazepine, midazolam and triazolam, nefazodone, cyclosporine, calcium antagonists, quinidine, lipid-lowering drugs, HIV-1 protease inhibitors (Wrighton and Thummel, 2000). It is an inducible enzyme, and clinically the most important inducers are carbamazepine and rifampicin. It is the source of numerous clinically important drug–drug interactions especially including substrates that are potent or effective inhibitors such as erythromycin, ketoconazole, nefazodone, norfluoxetine (active metabolite of fluoxetine) and the HIV-1 protease inhibitors.
4. Pharmacokinetics and drug serum concentrations and clinical response of citalopram Citalopram is administered as a racemic mixture and the inhibition of serotonin reuptake is associated almost exclusively by the S-enantiomer (Hyttel et al., 1992). Citalopram is N-demethylated to N-desmethylcitalopram partially by CYP2C19 and CYP3A4 (Gram et al., 1993; Sindrup et al., 1993; Kobayashi et al., 1997; Rochat et al., 1997; von Moltke et al., 1999; Olesen and Linnet, 1999) and desmethylcitalopram is further N-demethylated by CYP2D6 (Sindrup et al., 1993). The two metabolites do not contribute to the antidepressant effect. Citalopram is completely absorbed from the intestine (Kragh-Sørensen et al., 1981). The total clearance following oral intake is about 26 l / h in extensive metabolizers with regard to CYP2C19 and about half this value in poor metabolizers (Sindrup et al., 1993) the volume of distribution is about 14 l / kg and the elimination half-life for the active compound is 33 h (Kragh-Sørensen et al., 1981; Sindrup et al., 1993) and somewhat longer in poor metabolizers. At recommended clinical doses of citalopram between 20 and 60 mg / day, plasma levels of racemic citalopram and desmethylcitalopram range from 9 to 200 ng / ml and 10 to 105 ng / ml, respectively (summarized by Buur Rasmussen and Brøsen, 2000). In the dose range from 10 to 60 mg / day, citalopram and its two demethylated metabolites displayed linear pharmacokinetics (Baumannn and Larsen, 1995). When using a stereoselective method, concentration ranges of S-citalopram: 9–106 ng / ml, Rcitalopram: 20–186 ng / ml, S-desmethylcitalopram: 4–38 ng / ml and R-desmethylcitalopram: 3–75 ng / ml were observed (Rochat et al., 1995). Thus the mean ratio between S- and R-citalopram was 0.56 with a range of 0.32–0.97, and this was later confirmed (Sidhu et al., 1997). This suggests a more rapid elimination of the active S-enantiomer compared with the inactive R-enantiomer, and recent in vitro studies support this (Rochat et al., 1997). Numerous studies have been conducted aiming at establishing a correlation between citalopram serum concentration and effect in the treatment of depression (Baumann, 1996). Thus there is no evidence for a therapeutic window or a concentration threshold above which there is an increased risk for adverse effects (Dufour et al., 1987; Baumannn et al., 1996; Bjerkenstedt et al., 1985).
However, one case report on a severely depressed woman showed that showed that a dose of 20 mg / day had higher efficacy than a dose of 40 mg / day, suggesting that after all there may be a kind of a therapeutic window (Benazzi, 1996).
5. SSRIs and pharmacokinetic interactions The drug discovery and development process for citalopram and other SSRIs started in the early 1970s, and during that time no one thought of investigating their relationship with cytochrome P450. Thus once the SSRIs were approved for marketing in the late 1980s virtually nothing was known about which CYPs that catalyse their biotransformation, nor which CYPs they are influencing by SSRI administration. It came as a big surprise when case reports showed interactions between fluoxetine and CYP2D6 substrates such as desipramine and nortriptyline (Vaughan, 1988), and paroxetine and the model drug sparteine (Brøsen et al., 1991). In essence, extensive metabolizers of the CYP2D6 type changed phenotype to poor metabolizers during fluoxetine and paroxetine intake, suggesting that the two SSRIs are potent inhibitors of CYP2D6. The very early clinical observations prompted both in vitro and in vivo investigations on this matter. The early studies (Brøsen and Skjelbo, 1991; Skjelbo and Brøsen, 1992; Crewe et al., 1992) confirmed that fluoxetine, its active metabolite norfluoxetine and paroxetine are potent inhibitors of CYP2D6 and that citalopram, fluvoxamine and sertraline are weak to moderate inhibitors unlikely to cause clinically important interactions with substrates of this enzyme. A very recent study showed, that S-citalopram (Greenblatt et al., 2000) as expected also is a very weak inhibitor of CYP2D6 in vitro. The studies were subsequently extended to include also other CYPs, and we now have a very good picture of the relationship between CYP and SSRIs. Thus to summarize, fluvoxamine is a potent inhibitor of both CYP1A2 and CYP2C19 and a moderate inhibitor of CYP2C9 (Madsen et al., 2001) fluoxetine, norfluoxetine and paroxetine are potent inhibitors of CYP2D6 and norfluoxetine is a moderate inhibitor of CYP3A4 (Table 1). The original work on which this ultrashort account is based is cited in a number of comprehensive reviews written by some of the active researchers in the field (Brøsen, 1993, 1998; Brøsen and Rasmussen, 1996; Baumannn, 1996; Greenblatt et al., 1998, 1999). Below there is a more detailed account on the more recent work and observations regarding citalopram.
6. Potential pharmacokinetic interactions with citalopram caused by other drugs The fact that citalopram is metabolised by more than one CYP, notably CYP2C19 and CYP3A4, means that inhibition of its biotransformation by other drugs is less
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Table 1 Relative inhibitory potency of the SSRIs with respect to four of the most important CYPs SSRI
CYP 2D6 b KI (mmol / l) Dextromethorphan probe
CYP 3Ab KI (mmol / l) Alprazolam probe
CYP 2C19 b KI (mmol / l) S-Mephenytoin probe
CYP 1A2 IC 50 c (mM) Paracetamol probe
Citalopram Desmethyl-citalopram Fluoxetine Norfluoxetine Fluvoxamine Paroxetine Sertraline
7 6 0.17 0.19 1.8 0.065 1.5
a
87.3 55.8 5.2 1.1
.100 .100 .100 .100 0.2 45 70
a
83.3 11.1 10.2 39.4 23.8
]
7.5 2.0
Adapted with permission from Naranjo et al. (1999). a Minimal or no inhibition. b KI , inhibitor constant. c IC 50 , the concentration of the inhibitor which reduced the formation of a metabolite by 50% where lower values indicate higher inhibitory potency.
likely. Besides citalopram has a wide margin of safety, and even if there was a change in the plasma levels of citalopram caused by the concomitant intake of other drugs this would be unlikely to cause clinical complications. In the literature there is one possible exception. In two patients, a substitution of the CYP inducing agent carbamazepine with the much less inducing oxcarbazepine resulted in a threefold and eightfold increase in citalopram levels, which in one of the patients caused increased anxiety and tremor (Leinonen et al., 1996a). Daily intake of 800 mg of cimetidine, a well-known universal CYP inhibitor, resulted in an average increase in the steady-state plasma concentration of citalopram of 41% in 12 healthy subjects (Priskorn et al., 1997a). Leinonen reported moderate increases (about 20%) in citalopram steady-state concentrations in patients taking various antipsychotics and benzodiazepines (Leinonen et al., 1996b). However, this was not a controlled study; patients were taking varied doses of all medications and there were no before and after serum levels, which makes it difficult to control for the large interindividual variation observed in serum citalopram concentrations. Comedication with a single oral dose of 50 mg of the potent CYP2D6 inhibitor levomepromazine (Gram et al., 1993) did not change the serum concentration of citalopram, but increased the level of desmethylcitalopram, consistent with this metabolite being further metabolized by CYP2D6. Concomitant intake of tricyclic antidepressants resulted in a 44% increase in citalopram levels. The most pronounced effect among the tricyclic antidepressants was seen with clomipramine (Leinonen et al., 1996b; Lepola et al., 1994), and this is consistent with this drug being a relatively potent inhibitor of both CYP2C19 and CYP2D6 (Nielsen et al., 1992). In seven depressed women (Bondolfi et al., 1996) who took citalopram 40 mg / day there was an increase in the average plasma levels of S-citalopram from 27 to 83 ng / ml and of R-citalopram from 55 to 98 ng / ml during concomitant intake of fluvoxamine 50 mg / day. Accordingly the S: R ratio increased from an average of 0.48 to 0.84, suggesting, that the CYPs involved in metabolism of S-citalopram are more affected by fluvoxamine than those involved in the oxidation of R-citalopram. The same applies to fluoxetine,
where a clinical study of 11 patients taking citalopram 40 mg / day experienced a doubling of their S-citalopram steady-state concentration and a 50% increase of their R-citalopram levels during concomitant intake of fluoxetine 10 mg / day (Bondolfi et al., 2000). The interactions are most certainly due to fluvoxamine and fluoxetine both being potent inhibitors of CYP2C19 in vivo (Jeppesen et al., 1996). Co-administration of a single oral dose of ketoconazole, a well-known CYP3A4 inhibitor, did not result in a statistically significant change in the pharmacokinetics of a single oral dose of 40 mg citalopram (Gutierrez and Abramowitz, 2001).
7. Potential interactions caused by citalopram As mentioned earlier, citalopram does not inhibit CYP or it does so only very moderately in vitro. A number of studies with healthy subjects or patients have recently been performed to verify that this holds true also in vivo: CYP1A2 (clozapine and theophylline), CYP2C9 (warfarin), CYP2C19 (imipramine and mephenytoin), CYP2D6 (sparteine, imipramine and amitriptyline), CYP3A4 (carbamazepine and triazolam) and CYP2C9 (warfarin).
7.1. Tricyclic antidepressants There has been one case report which noted increased serum drug concentrations of clomipramine, alprazolam and citalopram only after citalopram was added to the two other drugs, possibly due to inhibition of CYP2D6, which is largely responsible for the metabolism of clomipramine, and CYP 3A4, which metabolizes alprazolam (Lepola et al., 1994). A 53-year-old woman committed suicide by taking an overdose of trimipramine (Musshoff et al., 1999), but the role of concomitant intake of citalopram was not clear. One study by Gram et al. (1993) showed that citalopram caused a 50% increase in the single-dose area under the serum concentration–time curve of the desipramine metabolite of imipramine in 8 healthy male volunteers after 40 mg / day citalopram for 10 days. The increase in the parent
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drug concentration did not reach a level of statistical significance (Gram et al., 1993), and this is partially explained by the fact, that citalopram despite being a substrate for CYP2C19 does not inhibit the enzyme at clinically relevant doses (Jeppesen et al., 1996). Clinically, however, one case study involving a patient who was experiencing ataxia, confusion and lightheadedness secondary to supratherapeutic levels of desipramine after paroxetine augmentation, demonstrated reduced desipramine levels and toxicity after switching to citalopram (Ashton, 2000). Desipramine toxicity was likely caused by CYP2D6 inhibition by paroxetine, indicating that this blockade might be minimized with use of citalopram. Citalopram appeared to have no effect on amitriptyline and nortriptyline plasma concentrations in five case studies (Baettig et al., 1993). Somewhat surprisingly a near doubling of N-desmethyl clomipramine was reported in a patient who both took clomipramine, 75 mg / day and citalopram 40 mg / day (Haffen et al., 1999). This could be due to a relatively low CYP2D6 content because the patient was a heterozygous carrier of the nonfunctional CYP2D6*6.
7.2. Serotonin syndrome Serotonin syndrome is a rare but serious event that can occur when medications that act to increase serotonin at the synaptic junction are coadministered (Sternbach, 1991). Serotonin syndrome is characterized by a constellation of symptoms that include mental status changes, agitation, myoclonus, hyperreflexia, sweating, shivering, tremor, diarrhea, lack of coordination, and fever. There have been a few documented cases of serotonin syndrome with citalopram and moclobemide (Neuvonen et al., 1994; Guma et al., 1999), and one case after a citalopram– buspirone combination (Spigset and Adielsson, 1997). However, there is little information available about the comparative risk among the different SSRIs.
7.3. SSRIs There are no published in vivo examples of interactions between citalopram and other SSRIs.
7.4. Benzodiazepines Depression and anxiety are highly comorbid. Data from Maier and Falkai (1999) in a primary care setting found that the observed rate of comorbidity between anxiety and depression was almost five times higher than the expected rate of comorbidity as determined by the World Health Organization. Therefore, we would expect there to be a significant number of patients receiving combination pharmacotherapy for both disorders. There have been no case reports of the effects of citalopram on the pharmacokinetics of benzodiazepines. A recent controlled,
within-subjects study by Nolting compared acute-dose pharmacokinetics of triazolam 0.25 mg before and after 4 weeks of citalopram administration (20 mg / day in week 1; 40 mg / day for 3 weeks) and found no change in plasma triazolam AUC before and after citalopram, possibly indicating little inhibition of the CYP 3A4 enzyme (Nolting and Abramowitz, 2000). In a similar randomized placebo-controlled within-subjects study, citalopram did not cause any changes in the plasma AUC of alprazolam (n510), unlike fluoxetine, which caused a significant increase in the AUC of alprazolam (n511) [C.A. Naranjo, personal communication].
7.5. Antiepileptics /mood stabilizers Citalopram appears not to interact with carbamazepine in vivo. One study found no change in 35 days dosing (400 mg) carbamazepine pharmacokinetics before and after administration of citalopram 40 mg / day for 14 days (Møller et al., 2000a).
7.6. Antipsychotics Approximately 25% of schizophrenic patients have intervals of major depression during the course of their illness, making the issue of comedication with antidepressants of major importance. A randomized, placebo-controlled parallel study was carried out in 90 stabilized schizophrenic patients. Citalopram 40 mg / day was given as augmentation therapy with previously prescribed antipsychotics. No major alterations in plasma antipsychotic levels were discovered in any medication; haloperidol, chlorpromazine, zuclopenthixol, levomepromazine, ¨ thioridazine, and perphenazine (Syvalahti et al., 1997). In a non-randomized, open trial in five in-patients stabilized on clozapine, Taylor et al. (1998) found no change in clozapine concentrations after augmentation with 20 mg / day citalopram. However, a recent case report suggested otherwise. A schizophrenic man experienced sedation, new-onset fatigue, confusion, enuresis and hypersalivation secondary to supratherapeutic levels of clozapine after augmentation with 40 mg / day of citalopram (Borba and Henderson, 2000). Symptoms disappeared and clozapine levels dropped significantly after reduction of citalopram to 20 mg / day, suggestive of possible CYP1A2 or 3A4 blockade at the higher dose of citalopram. Avenoso, however, found no change in clozapine or risperidone serum levels after citalopram 40 mg / day augmentation in 15 schizophrenics stabilized on clozapine or risperidone for at least 6 months (Avenoso et al., 1998).
7.7. Lithium Citalopram does not appear to alter the kinetics of lithium when the two are coadministered (Gram et al., 1993), however a study by Baumannn et al. (1996)
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suggested that lithium augmentation in depression was an effective treatment in non-responders to citalopram alone.
7.8. Other non-CNS drugs Citalopram did not change the pharmacokinetics of theophylline, a CYP1A2 substrate (Møller et al., 2000b).
7.9. Drugs used in the elderly At least 4% of elderly patients living in the community suffer from a major depressive disorder and some 15% from less severe forms of depressive illness. Furthermore, psychiatric and physical comorbidity is high in the aged and the incidence of depression may reach 40–50% in common medical disorders such as diabetes and cardiac insufficiency (Strnad and Bahro, 1999). It is important to know how drugs commonly used in the elderly will interact with antidepressant medications. A study in 18 healthy nonsmoking white men (ages 19–28) compared the pharmacokinetics of both acute dose and chronic (4-day) administration of selegiline (10 mg / day) after 10–14 days of citalopram 20 mg / day (Laine et al., 1997). Neither serum citalopram nor serum selegiline appeared to be affected by the other. Another recent study (Larsen et al., 2001) compared the renal clearance of acute digoxin before and after chronic citalopram 40 mg / day in thirteen healthy male and female volunteers (18–40 years old). Volunteers deficient in CYP2D6 and CYP2C19, as determined by metabolic phenotyping for poor metabolizers of sparteine and mephenytoin, were excluded. Citalopram did not have any significant effect on serum levels of digoxin, and this speaks against citalopram being an inhibitor of P-glycoprotein. In keeping with this, the mean plasma concentrations of another P-glycoprotein and CYP3A4 substrate, cyclosporine (Lown et al., 1997) at baseline in five patients treated with doses ranging from 75 to 225 mg twice daily was |220 and |210 ng / ml during citalopram 10–20 mg / day (Liston et al., 2000). An open, randomized, crossover study in healthy males compared the acute dose pharmacokinetics of warfarin before and after 21 days of citalopram (40 mg / day) in 12 healthy males (21–32 years old). Citalopram produced no changes in the pharmacokinetics of (R)- and (S)-warfarin, indicating no drug interactions via CYP1A2, CYP3A4 or CYP2C9 (Priskorn et al., 1997b). Citalopram produced a statistically significant increase in the maximum prothrombin time and the area under the prothrombin time–time curve, however this increase is not considered to be important in the clinical setting (Priskorn et al., 1997b).
7.10. Drugs of abuse There have been no case reports or controlled studies investigating the pharmacokinetic interaction between citalopram and alcohol. However, citalopram has been
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used in several studies as an adjunct in the treatment of alcohol dependence, where it seems to have clinical efficacy, and there appears to be no evidence for acute kinetic or dynamic interactions between alcohol and citalopram (Lader et al., 1986; Gorelick, 1989). Lack of potentiation of alcohol effects has been noted consistently in these studies. Interestingly, a placebo-controlled, randomized study found that pretreatment with citalopram was able to attenuate the psychological state produced by an acute dose of 3,4-methylenedioxymethamphetamine (MDMA) in 16 healthy volunteers (Liechti et al., 2000). MDMA is a recreational drug that produces heightened mood, increased self-confidence and extroversion. MDMA has been shown to release serotonin and dopamine in animal brains, suggesting a possible mechanism of action. Since citalopram acts by inhibiting serotonin reuptake, this is an example of a pharmacodynamic interaction between citalopram and another psychotropic medication. In a crossover study, eight healthy subjects (von Bahr et al., 2000) took either citalopram, 40 mg, fluvoxamine, 50 mg, or placebo on three separate occasions as single oral doses. The serum concentration of melatonin was determined at regular intervals for up 20 h following drug or placebo intake. Thus after fluvoxamine the area under the plasma concentration versus time curve increased nearly three times for melatonin compared with placebo whereas there was no statistically significant change following citalopram. The study suggests that fluvoxamine but not citalopram inhibits the CYP, possibly CYP1A2 and CYP2C19, responsible for the breakdown of melatonin.
8. Conclusion In conclusion, citalopram is neither the source nor the cause of any clinically important pharmacokinetic drug– drug interactions. Other SSRIs, paroxetine, fluoxetine, and fluvoxamine, display greater in vitro inhibition of CYP3A4, CYP2D6, CYP2C19 and CYP1A2 than citalopram, and this is also reflected in their drug interaction profiles (Sproule et al., 1997). This suggests that citalopram may be a better choice than the other SSRIs in patients who are at high risk of experiencing metabolic drug interactions, for example patients on multidrug therapy, particularly elderly patients who may be more sensitive to small elevations in drug concentrations.
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