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In vitro metabolism of citalopram by monoamine oxidase B in human blood
European Neuropsychopharmacology 11 (2001) 75–78 www.elsevier.com / locate / euroneuro
Short communication
In vitro metabolism of citalopram by monoamine oxidase B in human blood Markus Kosel, Marlyse Amey, Anne-Catherine Aubert, Pierre Baumann* ´ Unite´ de Biochimie et Psychopharmacologie Clinique, Departement Universitaire de Psychiatrie Adulte, CH-1008 Prilly-Lausanne, Switzerland Received 2 August 2000; accepted 18 October 2000
Abstract The metabolism of the antidepressant citalopram (CIT) by monoamine oxidase B (MAO-B) was studied in vitro. In incubations with blood of nine healthy volunteers R-(P 5 0.015) and S-(P 5 0.0034) CIT propionic acid (CITPROP) production was correlated with the number of platelets. S-CITPROP production was 5.6 times higher than R-CITPROP production and in incubations containing the MAO-B inhibitor deprenyl, racemic CITPROP production was diminished to 9.1%. To our knowledge, this is the first time that MAO-B activity in blood is shown with an antidepressant as substrate. As MAO is strongly expressed in human brain, this observation suggests that this enzymatic system may be implicated in drug metabolism in the CNS. 2001 Elsevier Science B.V. All rights reserved. Keywords: Citalopram; Human; Monoamine oxidase; Blood; In vitro; Drug metabolism
1. Introduction The antidepressant citalopram (CIT), which belongs to the group of the selective serotonin reuptake inhibitors (SSRI), undergoes, in the liver, stereoselective biotransformation catalysed by cytochrome P-450 (EC 1.14.14.1, CYP) and monoamine oxidase (MAO, EC 1.4.3.4). The pharmacological activity of CIT resides primarily in its S-enantiomer (Hyttel et al., 1992). The main metabolic pathway of CIT in liver, N-demethylation, is catalysed by CYP2C19, CYP3A4 and CYP2D6, and leads to the stereoselective formation of demethylcitalopram (DCIT) and didemethylcitalopram (DDCIT) (Rochat et al., 1997; Olesen and Linnet, 1999). By a minor pathway, MAO catalyses the transformation of CIT to the hypothetical intermediate citalopram-aldehyde (CITALD). CITALD is then dehydrogenated, presumably by aldehyde oxidase (EC 1.2.3.1, AO), to yield a CIT propionic acid derivative, CITPROP (Rochat et al., 1998). In a detailed study about the metabolism of CIT, 75% of labelled CIT was recovered *Corresponding author. Tel.: 141-21-64-36434; fax: 141-21-6436444. E-mail address: [email protected] (P. Baumann).
after 17 days in the urine of volunteers. Most of this radioactivity (75%) was made up of CIT, D-CIT and DD-CIT and / or their glucuroconjugated metabolites. Twelve percent was found to be the glucuronidated form of CITPROP and 7% was CIT-N-oxide (Dalgaard and Larsen, 1999). In one study, after a single dose of intravenous CIT in human volunteers, CITPROP appeared to be the main metabolite (Seifritz et al., 1996). In human blood, only platelets contain MAO and only the MAO-B isoenzyme is expressed. Platelet MAO-B has the same amino acid sequence as human brain MAO-B (Chen et al., 1993). As in the brain, MAO is implicated in the metabolism of monoamine neurotransmitters such as dopamine, serotonin and noradrenaline, MAO activity in platelets was extensively studied as a potential biological marker in psychiatric disease (Oreland and Hallman, 1995; Wirz-Justice, 1988). MAO has only for a short time been considered as a drug and a xenobiotic metabolising enzyme (Testa, 1995; Strolin Benedetti and Tipton, 1998). In the present study, we investigated the hypothesis of the presence of CIT metabolism by MAO-B in human blood. In an assay using kynuramine as substrate, MAO activity measured in whole blood reflected the activity measured in purified platelets (van Kempen et al., 1985).
0924-977X / 01 / $ – see front matter 2001 Elsevier Science B.V. All rights reserved. PII: S0924-977X( 00 )00128-0
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M. Kosel et al. / European Neuropsychopharmacology 11 (2001) 75 – 78
Preliminary experiments in our laboratory (not shown) yielded no evidence for a biotransformation of CIT to CITPROP in isolated platelets, even if in control experiments, kynuramine was found to be metabolised by MAOB. Therefore, the in vitro production of R- and S-CITPROP in whole blood was measured. The production of the presumed metabolite CITALD was not investigated. Produced aldehyde metabolites are usually unstable and not detected in in vitro assays, as the biological samples often contain the aldehyde metabolising enzymes (Beedham et al., 1995).
2. Experimental procedures The following drugs were gifts: the enantiomers of CIT (S-CIT and R-CIT), the racemates of CIT, DCIT DDCIT and CITPROP (Lundbeck AS, Copenhagen, Denmark), the internal standard S-flurbiprofen (Boots, Nottingham, UK). The following drugs and chemicals were obtained by commercial sources: R(2)-deprenyl (selegiline) (RBI, Natick, MA, USA); clorgyline, (Sigma, Buchs, Switzerland); methyliodide (Fluka, Buchs, Switzerland). Intravenous blood was collected from nine volunteers in EDTA containing standard sampling tubes (S-monovette KE, Sarstedt, Sevelen, Switzerland). None of the volunteers were under the influence of known MAO-inhibiting medication. Blood cell, platelet count and haemoglobin concentration measures were performed automatically with a Celltrak 12 analyser (Nova Biomedical, Waltham, MA, USA). All incubations were done in triplicate. Working solutions of substrates contained CIT or DCIT at a concentration of 10 mM dissolved in phosphate buffer. Of the specific inhibitors MAO-A (clorgyline) and MAO-B (deprenyl), working solutions were prepared containing 0.5 mM clorgyline or selegiline dissolved in 2% DMSO and 98% H 2 O (v / v). As it had been shown that DMSO at a final concentration of 5% (v / v) in the incubation mixture had no influence on the catalytic activity of MAO (Thull and Testa, 1994), the influence of DMSO in our incubations was not investigated (the final concentration of DMSO in our incubations was 0.002%). The anticoagulated blood samples were kept at room temperature until preincubation which took place maximally 2 h after collection. During 15 min, the blood was prewarmed at 378C in a waterbath without substrate or inhibitors. A 4-ml aliquot of one or both working solutions of the specific inhibitors was then added to the blood samples (aliquots of 3.8 ml; final concentrations of the inhibitors, 500 nM each). After 15 min at 378C, 200 ml of CIT or DCIT working solution were added. The final concentration of the substrate was 0.5 mM when not otherwise indicated. During another 15 min, the samples remained in the water bath at 378C. They were then transferred to a hybridisation oven heated at 378C and were constantly rotated. The reaction was stopped after 6 h by
putting the samples in ice. After 15 min at 48C, the samples were centrifuged at 30003g during 5 min at 48C. Of the plasma, 1.8 ml was taken and 0.3 ml of 1 M HCl was added. These samples were kept at 2208C until analysis. CITPROP in human plasma was measured by a stereoselective HPLC method on a HP HPLC 1100 system (Hewlett-Packard, Meyrin, Switzerland) (Rochat et al., 1995).
3. Results and discussion CITPROP production in whole blood incubated with CIT was linear from 3 h to at least 9 h and at a final concentration of CIT varying from 67.5 to 500 mM. At concentrations above 1 mM CIT, haemolysis occurred and measurement of CITPROP was therefore impossible. In Fig. 1, R- and S-CITPROP production in blood from nine subjects is shown as a function of the platelet count. Spearman correlation statistics were performed. R-CITPROP production was significantly correlated with the platelet count (R 2 50.59; P50.015) but not with red blood cells (RBCs) or white blood cells. S-CITPROP production, however, was correlated with the platelet count (R 2 50.73; P50.0034) and negatively with RBCs (R 2 50.61; P5 0.013). These findings are in line with the fact that the localisation of MAO-B in human blood is in the platelets. The negative correlation between S-CITPROP production and RBCs could be explained by the fact that RBCs contain enzymatic systems (Helander, 1993) which could catalyse the production of S-CIT-alcohol or other metabolites from S-CITALD. Compared to R-CIT, the higher R 2 value for S-CIT suggests that this enantiomer is more selectively metabolised to R-CITPROP. Specific production of R-CITPROP and S-CITPROP in the blood of the nine volunteers amounted to 1661.6 and 90630 fmol / min per ml plasma normalised to 10 5 platelets / mm 3 (means6S.D.), respectively. These results suggest that S-CIT is preferentially a substrate of MAO-B in comparison to R-CIT. CIT was incubated with clorgyline or deprenyl and without inhibitors in the blood of two volunteers. Clorgyline inhibited CITPROP production only very slightly (5.5%), whereas deprenyl at the same concentration strongly inhibited the activity of MAO-B: the production of CITPROP was reduced to 9.6% of the levels measured without deprenyl. In these two subjects, 5.7 times more R- and 7.6 times more S-CITPROP was produced when DCIT was used as substrate compared to CIT. We thus confirmed by our study that MAO-B produces S-CITPROP at a higher rate than R-CITPROP when CIT is used as a substrate, and that DCIT is a better substrate for MAO-B than CIT. These findings have already been shown in human liver microsomes (Rochat et al., 1998). The concentration of CIT in our incubations was 0.5
M. Kosel et al. / European Neuropsychopharmacology 11 (2001) 75 – 78
77
Fig. 1. R- and S-CITPROP production in human blood according to the number of platelets. Each point corresponds to the mean of three incubations, vertical bars indicate6S.D. Linear regression curves are presented.
mM which corresponds to 0.163 mg / ml CIT in plasma. Such a concentration is roughly 1000 times higher than concentrations of CIT achieved in patients treated routinely with CIT (Baumann, 1996; Noble and Benfield, 1997). The clinical chemist implicated in the assay of CIT may conclude that there is little risk for a significant biotransformation of CIT to CITPROP in whole blood stored at room temperature for a few hours. According to our knowledge, this is the first time that in vitro MAO-B activity in blood is shown with an antidepressant as substrate. As the metabolism of CIT by MAO was described in human liver (Rochat et al., 1998), the present study adds evidence to the hypothesis that there may be a local metabolism of CIT and DCIT by MAO-B in human brain. Therefore, besides cytochrome P-450, MAO also has to be considered as an enzymatic system implicated in drug metabolism in the CNS (Ravindranath, 1998).
Acknowledgements This study was supported by the Swiss National Science Foundation (Grants 32-42076.94 and 32-53717.98). We are grateful to Mrs K. Powell Golay for the preparation of the manuscript.
References Baumann, P., 1996. Pharmacology and pharmacokinetics of citalopram and other SSRIs. Int. Clin. Psychopharmacol. 11, S5–S11. Beedham, C., Peet, C.F., Panoutsopoulos, G.I., Carter, H., Smith, J.A.,
1995. Role of aldehyde oxidase in biogenic amine metabolism. Progr. Brain Res. 106, 6–14. Chen, K., Wu, H.F., Shih, J.C., 1993. The deduced amino acid sequences of human platelet and frontal cortex monoamine oxidase B are identical. J. Neurochem. 61, 187–190. Dalgaard, L., Larsen, C., 1999. Metabolism and excretion of citalopram in man: identification of O-acyl- and N-glucuronides. Xenobiotica 29, 1033–1041. Helander, A., 1993. Aldehyde dehydrogenase in blood: distribution, characteristics and possible use as marker of alcohol misuse. Alcohol Alcoholism 28, 135–146. Hyttel, J., Bøgesø, K.P., Perregaard, J., Sanchez, C., 1992. The pharmacological effect of citalopram resides in the (S)-(1)- enantiomer. J. Neural Transmission 88, 157–160. Noble, S., Benfield, P., 1997. Citalopram: a review of its pharmacology, clinical efficacy and tolerability in the treatment of depression. CNS Drugs 8, 410–431. Olesen, O.V., Linnet, K., 1999. Studies on the stereoselective metabolism of citalopram by human liver microsomes and cDNA-expressed cytochrome P450 enzymes. Pharmacology 59, 298–309. Oreland, L., Hallman, J., 1995. The correlation between platelet MAO activity and personality: short review of findings and discussion on possible mechanisms. Progr. Brain Res. 106, 77–84. Ravindranath, V., 1998. Metabolism of xenobiotics in the central nervous system: implications and challenges. Biochem. Pharmacol. 56, 547– 551. Rochat, B., Amey, M., van Gelderen, H., Testa, B., Baumann, P., 1995. Determination of the enantiomers of citalopram, its demethylated and propionic acid metabolites in human plasma by chiral HPLC. Chirality 7, 389–395. Rochat, B., Amey, M., Gillet, M., Meyer, U.A., Baumann, P., 1997. Identification of three cytochrome P450 isozymes involved in Ndemethylation of citalopram enantiomers in human liver microsomes. Pharmacogenetics 7, 1–10. Rochat, B., Kosel, M., Boss, G., Testa, B., Gillet, M., Baumann, P., 1998. Stereoselective biotransformation of the selective serotonin reuptake inhibitor citalopram and its demethylated metabolites by monoamine oxidases in human liver. Biochem. Pharmacol. 56, 15–23. ¨ Seifritz, E., Baumann, P., Muller, M.J., Annen, O., Amey, M., Hemmeter, U., Hatzinger, M., Chardon, F., Holsboer-Trachsler, E., 1996. Neuroendocrine effects of a 20-mg citalopram infusion in healthy males — a
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M. Kosel et al. / European Neuropsychopharmacology 11 (2001) 75 – 78
placebo-controlled evaluation of citalopram as 5-HT function probe. Neuropsychopharmacology 14, 253–263. Strolin Benedetti, M., Tipton, K.F., 1998. Monoamine oxidases and related amine oxidases as phase l enzymes in the metabolism of xenobiotics. J. Neural Transmission 52, S149–S71. Testa, B., 1995. In: The Metabolism of Drugs and Other Xenobiotics. Academic Press, London. Thull, U., Testa, B., 1994. Screening of unsubstituted cyclic compounds
as inhibitors of monoamine oxidase. Biochem. Pharmacol. 47, 2307– 2310. van Kempen, G.M., van Brussel, J.L., Pennings, E.J., 1985. Assay of platelet monoamine oxidase in whole blood. Clin. Chim. Acta 153, 197–202. Wirz-Justice, A., 1988. Platelet research in psychiatry. Experientia 44, 145–152.
Short communication
In vitro metabolism of citalopram by monoamine oxidase B in human blood Markus Kosel, Marlyse Amey, Anne-Catherine Aubert, Pierre Baumann* ´ Unite´ de Biochimie et Psychopharmacologie Clinique, Departement Universitaire de Psychiatrie Adulte, CH-1008 Prilly-Lausanne, Switzerland Received 2 August 2000; accepted 18 October 2000
Abstract The metabolism of the antidepressant citalopram (CIT) by monoamine oxidase B (MAO-B) was studied in vitro. In incubations with blood of nine healthy volunteers R-(P 5 0.015) and S-(P 5 0.0034) CIT propionic acid (CITPROP) production was correlated with the number of platelets. S-CITPROP production was 5.6 times higher than R-CITPROP production and in incubations containing the MAO-B inhibitor deprenyl, racemic CITPROP production was diminished to 9.1%. To our knowledge, this is the first time that MAO-B activity in blood is shown with an antidepressant as substrate. As MAO is strongly expressed in human brain, this observation suggests that this enzymatic system may be implicated in drug metabolism in the CNS. 2001 Elsevier Science B.V. All rights reserved. Keywords: Citalopram; Human; Monoamine oxidase; Blood; In vitro; Drug metabolism
1. Introduction The antidepressant citalopram (CIT), which belongs to the group of the selective serotonin reuptake inhibitors (SSRI), undergoes, in the liver, stereoselective biotransformation catalysed by cytochrome P-450 (EC 1.14.14.1, CYP) and monoamine oxidase (MAO, EC 1.4.3.4). The pharmacological activity of CIT resides primarily in its S-enantiomer (Hyttel et al., 1992). The main metabolic pathway of CIT in liver, N-demethylation, is catalysed by CYP2C19, CYP3A4 and CYP2D6, and leads to the stereoselective formation of demethylcitalopram (DCIT) and didemethylcitalopram (DDCIT) (Rochat et al., 1997; Olesen and Linnet, 1999). By a minor pathway, MAO catalyses the transformation of CIT to the hypothetical intermediate citalopram-aldehyde (CITALD). CITALD is then dehydrogenated, presumably by aldehyde oxidase (EC 1.2.3.1, AO), to yield a CIT propionic acid derivative, CITPROP (Rochat et al., 1998). In a detailed study about the metabolism of CIT, 75% of labelled CIT was recovered *Corresponding author. Tel.: 141-21-64-36434; fax: 141-21-6436444. E-mail address: [email protected] (P. Baumann).
after 17 days in the urine of volunteers. Most of this radioactivity (75%) was made up of CIT, D-CIT and DD-CIT and / or their glucuroconjugated metabolites. Twelve percent was found to be the glucuronidated form of CITPROP and 7% was CIT-N-oxide (Dalgaard and Larsen, 1999). In one study, after a single dose of intravenous CIT in human volunteers, CITPROP appeared to be the main metabolite (Seifritz et al., 1996). In human blood, only platelets contain MAO and only the MAO-B isoenzyme is expressed. Platelet MAO-B has the same amino acid sequence as human brain MAO-B (Chen et al., 1993). As in the brain, MAO is implicated in the metabolism of monoamine neurotransmitters such as dopamine, serotonin and noradrenaline, MAO activity in platelets was extensively studied as a potential biological marker in psychiatric disease (Oreland and Hallman, 1995; Wirz-Justice, 1988). MAO has only for a short time been considered as a drug and a xenobiotic metabolising enzyme (Testa, 1995; Strolin Benedetti and Tipton, 1998). In the present study, we investigated the hypothesis of the presence of CIT metabolism by MAO-B in human blood. In an assay using kynuramine as substrate, MAO activity measured in whole blood reflected the activity measured in purified platelets (van Kempen et al., 1985).
0924-977X / 01 / $ – see front matter 2001 Elsevier Science B.V. All rights reserved. PII: S0924-977X( 00 )00128-0
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M. Kosel et al. / European Neuropsychopharmacology 11 (2001) 75 – 78
Preliminary experiments in our laboratory (not shown) yielded no evidence for a biotransformation of CIT to CITPROP in isolated platelets, even if in control experiments, kynuramine was found to be metabolised by MAOB. Therefore, the in vitro production of R- and S-CITPROP in whole blood was measured. The production of the presumed metabolite CITALD was not investigated. Produced aldehyde metabolites are usually unstable and not detected in in vitro assays, as the biological samples often contain the aldehyde metabolising enzymes (Beedham et al., 1995).
2. Experimental procedures The following drugs were gifts: the enantiomers of CIT (S-CIT and R-CIT), the racemates of CIT, DCIT DDCIT and CITPROP (Lundbeck AS, Copenhagen, Denmark), the internal standard S-flurbiprofen (Boots, Nottingham, UK). The following drugs and chemicals were obtained by commercial sources: R(2)-deprenyl (selegiline) (RBI, Natick, MA, USA); clorgyline, (Sigma, Buchs, Switzerland); methyliodide (Fluka, Buchs, Switzerland). Intravenous blood was collected from nine volunteers in EDTA containing standard sampling tubes (S-monovette KE, Sarstedt, Sevelen, Switzerland). None of the volunteers were under the influence of known MAO-inhibiting medication. Blood cell, platelet count and haemoglobin concentration measures were performed automatically with a Celltrak 12 analyser (Nova Biomedical, Waltham, MA, USA). All incubations were done in triplicate. Working solutions of substrates contained CIT or DCIT at a concentration of 10 mM dissolved in phosphate buffer. Of the specific inhibitors MAO-A (clorgyline) and MAO-B (deprenyl), working solutions were prepared containing 0.5 mM clorgyline or selegiline dissolved in 2% DMSO and 98% H 2 O (v / v). As it had been shown that DMSO at a final concentration of 5% (v / v) in the incubation mixture had no influence on the catalytic activity of MAO (Thull and Testa, 1994), the influence of DMSO in our incubations was not investigated (the final concentration of DMSO in our incubations was 0.002%). The anticoagulated blood samples were kept at room temperature until preincubation which took place maximally 2 h after collection. During 15 min, the blood was prewarmed at 378C in a waterbath without substrate or inhibitors. A 4-ml aliquot of one or both working solutions of the specific inhibitors was then added to the blood samples (aliquots of 3.8 ml; final concentrations of the inhibitors, 500 nM each). After 15 min at 378C, 200 ml of CIT or DCIT working solution were added. The final concentration of the substrate was 0.5 mM when not otherwise indicated. During another 15 min, the samples remained in the water bath at 378C. They were then transferred to a hybridisation oven heated at 378C and were constantly rotated. The reaction was stopped after 6 h by
putting the samples in ice. After 15 min at 48C, the samples were centrifuged at 30003g during 5 min at 48C. Of the plasma, 1.8 ml was taken and 0.3 ml of 1 M HCl was added. These samples were kept at 2208C until analysis. CITPROP in human plasma was measured by a stereoselective HPLC method on a HP HPLC 1100 system (Hewlett-Packard, Meyrin, Switzerland) (Rochat et al., 1995).
3. Results and discussion CITPROP production in whole blood incubated with CIT was linear from 3 h to at least 9 h and at a final concentration of CIT varying from 67.5 to 500 mM. At concentrations above 1 mM CIT, haemolysis occurred and measurement of CITPROP was therefore impossible. In Fig. 1, R- and S-CITPROP production in blood from nine subjects is shown as a function of the platelet count. Spearman correlation statistics were performed. R-CITPROP production was significantly correlated with the platelet count (R 2 50.59; P50.015) but not with red blood cells (RBCs) or white blood cells. S-CITPROP production, however, was correlated with the platelet count (R 2 50.73; P50.0034) and negatively with RBCs (R 2 50.61; P5 0.013). These findings are in line with the fact that the localisation of MAO-B in human blood is in the platelets. The negative correlation between S-CITPROP production and RBCs could be explained by the fact that RBCs contain enzymatic systems (Helander, 1993) which could catalyse the production of S-CIT-alcohol or other metabolites from S-CITALD. Compared to R-CIT, the higher R 2 value for S-CIT suggests that this enantiomer is more selectively metabolised to R-CITPROP. Specific production of R-CITPROP and S-CITPROP in the blood of the nine volunteers amounted to 1661.6 and 90630 fmol / min per ml plasma normalised to 10 5 platelets / mm 3 (means6S.D.), respectively. These results suggest that S-CIT is preferentially a substrate of MAO-B in comparison to R-CIT. CIT was incubated with clorgyline or deprenyl and without inhibitors in the blood of two volunteers. Clorgyline inhibited CITPROP production only very slightly (5.5%), whereas deprenyl at the same concentration strongly inhibited the activity of MAO-B: the production of CITPROP was reduced to 9.6% of the levels measured without deprenyl. In these two subjects, 5.7 times more R- and 7.6 times more S-CITPROP was produced when DCIT was used as substrate compared to CIT. We thus confirmed by our study that MAO-B produces S-CITPROP at a higher rate than R-CITPROP when CIT is used as a substrate, and that DCIT is a better substrate for MAO-B than CIT. These findings have already been shown in human liver microsomes (Rochat et al., 1998). The concentration of CIT in our incubations was 0.5
M. Kosel et al. / European Neuropsychopharmacology 11 (2001) 75 – 78
77
Fig. 1. R- and S-CITPROP production in human blood according to the number of platelets. Each point corresponds to the mean of three incubations, vertical bars indicate6S.D. Linear regression curves are presented.
mM which corresponds to 0.163 mg / ml CIT in plasma. Such a concentration is roughly 1000 times higher than concentrations of CIT achieved in patients treated routinely with CIT (Baumann, 1996; Noble and Benfield, 1997). The clinical chemist implicated in the assay of CIT may conclude that there is little risk for a significant biotransformation of CIT to CITPROP in whole blood stored at room temperature for a few hours. According to our knowledge, this is the first time that in vitro MAO-B activity in blood is shown with an antidepressant as substrate. As the metabolism of CIT by MAO was described in human liver (Rochat et al., 1998), the present study adds evidence to the hypothesis that there may be a local metabolism of CIT and DCIT by MAO-B in human brain. Therefore, besides cytochrome P-450, MAO also has to be considered as an enzymatic system implicated in drug metabolism in the CNS (Ravindranath, 1998).
Acknowledgements This study was supported by the Swiss National Science Foundation (Grants 32-42076.94 and 32-53717.98). We are grateful to Mrs K. Powell Golay for the preparation of the manuscript.
References Baumann, P., 1996. Pharmacology and pharmacokinetics of citalopram and other SSRIs. Int. Clin. Psychopharmacol. 11, S5–S11. Beedham, C., Peet, C.F., Panoutsopoulos, G.I., Carter, H., Smith, J.A.,
1995. Role of aldehyde oxidase in biogenic amine metabolism. Progr. Brain Res. 106, 6–14. Chen, K., Wu, H.F., Shih, J.C., 1993. The deduced amino acid sequences of human platelet and frontal cortex monoamine oxidase B are identical. J. Neurochem. 61, 187–190. Dalgaard, L., Larsen, C., 1999. Metabolism and excretion of citalopram in man: identification of O-acyl- and N-glucuronides. Xenobiotica 29, 1033–1041. Helander, A., 1993. Aldehyde dehydrogenase in blood: distribution, characteristics and possible use as marker of alcohol misuse. Alcohol Alcoholism 28, 135–146. Hyttel, J., Bøgesø, K.P., Perregaard, J., Sanchez, C., 1992. The pharmacological effect of citalopram resides in the (S)-(1)- enantiomer. J. Neural Transmission 88, 157–160. Noble, S., Benfield, P., 1997. Citalopram: a review of its pharmacology, clinical efficacy and tolerability in the treatment of depression. CNS Drugs 8, 410–431. Olesen, O.V., Linnet, K., 1999. Studies on the stereoselective metabolism of citalopram by human liver microsomes and cDNA-expressed cytochrome P450 enzymes. Pharmacology 59, 298–309. Oreland, L., Hallman, J., 1995. The correlation between platelet MAO activity and personality: short review of findings and discussion on possible mechanisms. Progr. Brain Res. 106, 77–84. Ravindranath, V., 1998. Metabolism of xenobiotics in the central nervous system: implications and challenges. Biochem. Pharmacol. 56, 547– 551. Rochat, B., Amey, M., van Gelderen, H., Testa, B., Baumann, P., 1995. Determination of the enantiomers of citalopram, its demethylated and propionic acid metabolites in human plasma by chiral HPLC. Chirality 7, 389–395. Rochat, B., Amey, M., Gillet, M., Meyer, U.A., Baumann, P., 1997. Identification of three cytochrome P450 isozymes involved in Ndemethylation of citalopram enantiomers in human liver microsomes. Pharmacogenetics 7, 1–10. Rochat, B., Kosel, M., Boss, G., Testa, B., Gillet, M., Baumann, P., 1998. Stereoselective biotransformation of the selective serotonin reuptake inhibitor citalopram and its demethylated metabolites by monoamine oxidases in human liver. Biochem. Pharmacol. 56, 15–23. ¨ Seifritz, E., Baumann, P., Muller, M.J., Annen, O., Amey, M., Hemmeter, U., Hatzinger, M., Chardon, F., Holsboer-Trachsler, E., 1996. Neuroendocrine effects of a 20-mg citalopram infusion in healthy males — a
78
M. Kosel et al. / European Neuropsychopharmacology 11 (2001) 75 – 78
placebo-controlled evaluation of citalopram as 5-HT function probe. Neuropsychopharmacology 14, 253–263. Strolin Benedetti, M., Tipton, K.F., 1998. Monoamine oxidases and related amine oxidases as phase l enzymes in the metabolism of xenobiotics. J. Neural Transmission 52, S149–S71. Testa, B., 1995. In: The Metabolism of Drugs and Other Xenobiotics. Academic Press, London. Thull, U., Testa, B., 1994. Screening of unsubstituted cyclic compounds
as inhibitors of monoamine oxidase. Biochem. Pharmacol. 47, 2307– 2310. van Kempen, G.M., van Brussel, J.L., Pennings, E.J., 1985. Assay of platelet monoamine oxidase in whole blood. Clin. Chim. Acta 153, 197–202. Wirz-Justice, A., 1988. Platelet research in psychiatry. Experientia 44, 145–152.