Moclobemide poisoning: toxicokinetics and occurrence of serotonin toxicity

© 2003 Blackwell Publishing Ltd

Br J Clin Pharmacol

,

56

, 441–450

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Blackwell Science, Ltd

Oxford, UK

BJCPBritish Journal of Clinical Pharmacology

0306-5251Blackwell Publishing 2003

? 2003

56

4441450

Original Article

Moclobemide poisoningG. K. Isbister

et al.

Correspondence:

Dr Geoffrey K. Isbister, Discipline of Clinical Pharmacology,Level 5, Clinical Sciences Building, Newcastle Mater Misericordiae Hospital,Waratah NSW 2298, Australia. Tel.:

+

61 2 4921 1293; Fax:

+

61 2 4960 2088;E-mail: [email protected]

Received 26 August 2002, accepted 9 March 2003.

Moclobemide poisoning: toxicokinetics and occurrence of serotonin toxicity

Geoffrey K. Isbister,

1,2

L. P. Hackett,

3

Andrew H. Dawson,

1,2

Ian M. Whyte

1,2

& Anthony J. Smith

1

1

Discipline of Clinical Pharmacology, University Of Newcastle,

2

Department of Clinical Toxicology and Pharmacology, Newcastle Mater Misericordiae Hospital, Newcastle,

3

Clinical Pharmacology and Toxicology, The Western Australian Centre for Pathology and Medical Research, Perth, WA, Australia

Aims

To investigate the spectrum of toxicity of moclobemide overdose, the occur-rence of serotonin toxicity, and to estimate toxicokinetic parameters.

Methods

All moclobemide overdoses presenting over a 10-year period to the HunterArea Toxicology Service were reviewed. Clinical features, complications, length ofstay (LOS) and intensive care (ICU) admission rate were extracted from a standard-ized, prospectively collected database. Comparisons were made between moclobe-mide alone and moclobemide with a serotonergic coingestant poisoning. Serotonintoxicity was defined by a combination of Sternbach’s criteria and a clinical toxicol-ogist’s diagnosis. In five patients serial moclobemide concentrations were measured.Time to maximal plasma concentration (

T

max

), peak plasma concentration (

C

max

) andterminal elimination half-lives were estimated.

Results

Of 106 included patients, 33 ingested moclobemide alone, 21 ingestedmoclobemide with another serotonergic agent (in some cases in therapeutic doses)and 52 ingested moclobemide with a nonserotonergic agent. Eleven (55%) of 21patients coingesting a serotonergic drug developed serotonin toxicity, which wassignificantly more than one (3%) of 33 moclobemide-alone overdoses (odds ratio35, 95% confidence inteval 4, 307;

P

<

0.0001). In six of these 21 cases severeserotonin toxicity developed with temperature

>

38.5

∞

C and muscle rigidity requir-ing intubation and paralysis. The 21 patients had a significantly increased LOS (34 h)compared with moclobemide alone overdoses (12 h) (

P

<

0.0001) and a significantlyincreased ICU admission rate of 57%

vs.

3% (

P

<

0.0001). Time to peak plasmaconcentration was delayed in two patients where prepeak samples were obtained.

C

max

increased slightly with dose, but all three patients ingesting

≥

6 g vomited orhad charcoal. The mean elimination half-life of moclobemide in the five patients inwhom serial moclobemide concentrations were measured was 6.3 h and eliminationwas first order in all cases. There was no evidence of a dose-dependent increase inhalf-life.

Conclusions

The effects of moclobemide alone in overdose are minor, even withmassive ingestions. However, moclobemide overdose in combination with a sero-tonergic agent (even in normal therapeutic doses) can cause severe serotonin toxicity.The elimination half-life is prolonged by two to four times in overdose, comparedwith that found in healthy volunteers given therapeutic doses. This may be a resultof wide interindividual variation in overall elimination, also seen with therapeuticdoses, but appears not to be due to saturation of normal elimination pathways.

Keywords:

antidepressant, moclobemide, overdose, serotonin, toxicity,pharmacokinetics

Introduction

Moclobemide is a reversible and selective inhibitor ofmonoamine oxidase (MAO) type A [1, 2]. Controlledclinical trials have demonstrated it to be effective in thetreatment of depressive disorders. It, and other newer

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antidepressants, such as the selective serotonin reuptakeinhibitors (SSRIs), have increasingly been used for thetreatment of depression, instead of the older tricyclicantidepressants (TCAs) [1, 2].

There is conflicting opinion in the literature regardingthe safety of moclobemide in overdose based on casereports and small case series. Some authors have con-cluded that the drug does not cause major toxicity andis far safer than tricyclic antidepressants [3, 4]. However,there are reports of fatalities from moclobemide alone [5,6] and in combination with clomipramine [6–10], citalo-pram [8] and paroxetine [11]. Severe effects have beenreported with the combination of moclobemide and ven-lafaxine [12] and moclobemide and paroxetine in over-dose [13], all attributed to serotonin toxicity. It appearsthat most severe or fatal cases of moclobemide poisoningoccur with coingestion of serotonergic agents [8–10, 12,

13], increasing the likelihood that the effects are theresult of serotonin toxicity.

Two early series of moclobemide poisonings werereported prior to the widespread recognition of serotonintoxicity [4, 14]. One is from initial reports of 18 casesto the manufacturer [4] and the other is a small series ofreports to a poisons information centre [14]. Both con-clude that moclobemide is relatively nontoxic unlessingested with other agents. However, they do not iden-tify cases of serotonin toxicity, unlike many subsequentcase reports since, although many of the featuresdescribed in the poison centre series are consistent withthe diagnosis [14].

The kinetics of drugs in overdose are poorly defined,and moclobemide is no exception. Moclobemide is rap-idly and extensively metabolized, although only twometabolites are present to a large extent (Figure 1). Nei-

Figure 1

Diagram of moclobemide and its four major metabolic pathways with the important plasma and urinary metabolites illustrated. Not all 19 metabolites are included and those included are either marked by manufacturer’s numbers where available or the numbering system as per Jauch et al. [35]. Full structures of the parent and two major plasma metabolites are included. Circled percentages indicate the approximate percentage dose recovered in urine. M5 has some monoamine oxidase (MAO)-A-inhibitory activity, and M2 and M4 have been found to inhibit MAO-B in rat liver. Importantly, M15, the major plasma metabolite, is inactive. Modified from Jauch et al. 1990 [35].

M3 M10

Aromatic hydroxylation

<1% 3%

N-oxide metabolite, Ro 12-5637 or M5

Morpholine N-oxidation

3.5%

7%

M9 or Ro 11-1903

Deamination

11%

M7A

M2

Morpholine C-oxidation

M1

Major oxo-metabolite, Ro 12-8095 or M15

Multiple pathways and metabolites

M8

<1%

2%

M4 or Ro 16-3177

31%

MOCLOBEMIDE

M7B

P450 2C19

Moclobemide poisoning


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ther of the two metabolites have major inhibitory activityon MAO-A, but their kinetics are helpful in differentiatingpoor and extensive metabolizers. There are two reportsthat measure moclobemide and its metabolites followingoverdose [9, 15] and a number of deaths reported in whichdrug concentrations were measured [6, 11]. It is importantto determine the toxicokinetics of drugs to predict thetime course of their adverse effects so that safe observation,admission and discharge policies can be developed.

We present a cohort of moclobemide overdoses pre-senting to a tertiary hospital toxicology unit over a periodof 10 years. Serial drug concentrations were determinedin five cases associated with moderate to severe effects,and were modelled to estimate some toxicokineticparameters.

Methods

The Hunter Area Toxicology Service (HATS) is a regionaltoxicology unit situated at the Newcastle Mater Miseri-cordiae Hospital that serves a population of about 350 000people and is a tertiary referral centre for a further 150 000[16]. All toxicological presentations to emergency depart-ments in the region are either admitted to this unit ornotified to HATS and entered prospectively into a clinicaldatabase. A preformatted admission sheet is used by med-ical staff to collect data on admission [17] and this andadditional information from the medical record is enteredinto the database by two trained personnel blinded toany study hypotheses. Detailed demographic and clinicalinformation is recorded [18]. From the database, cases ofmoclobemide poisoning presenting between January 1992and June 2002 were identified.

Moclobemide overdose was defined as ingestion of

>

600 mg (maximum recommended daily dose of 300 mgtwice daily). Out of all admissions for moclobemidepoisoning only a patient’s first admission was included.Second and subsequent admissions were excluded toremove the potential bias of an individual susceptibilityto moclobemide.

The data reviewed included patient demography (sex,age), details of the moclobemide ingestion (estimated timeof ingestion, estimation of amount, coingestion), clinicalfeatures [heart rate (HR), blood pressure (BP), maximumtemperature, Glasgow coma score (GCS)], investigations,outcomes [mortality, seizures, coma (GCS

<

8), arrhyth-mias, hypotension, serotonin toxicity, length of stay (LOS)and intensive care (ICU) admission], and treatment.

Cases of serotonin toxicity were defined as those ful-filling Sternbach’s criteria where the attending clinical tox-icologist also diagnosed serotonin toxicity. Sternbach’scriteria are the presence of at least three of the followingclinical features: mental status changes (confusion, hypo-mania), agitation, myoclonus, hyperreflexia, diaphoresis,

shivering, tremor, diarrhoea, incoordination, fever in apatient commencing or having an increased dose of a sero-tonergic agent. In addition, other medical causes must beexcluded, and a neuroleptic not commenced or increasedin dose prior to the commencement of symptoms. The useof the additional inclusion criterion for serotonin toxicityrather than Sternbach’s criteria alone [19] is because Stern-bach’s criteria are not sensitive or specific enough for thediagnosis of serotonin toxicity in our unit’s experience[20]. Severe serotonin toxicity was defined as a temperature

>

38.5

∞

C or severe hypertonia and/or spontaneous clonusnecessitating muscle paralysis. Serotonergic coingestantsincluded all selective serotonin reuptake inhibitors, ven-lafaxine, all tricyclic antidepressants, other monoamineoxidase inhibitors, lithium and amphetamines.

Toxicokinetics

In five cases with moderate to severe poisoning serialmoclobemide concentrations were measured. Plasmaconcentrations of moclobemide and three of its metab-olites (Ro 12-8095, Ro 12-5637 and Ro 16-3177) werequantified by reverse phase high-performance liquidchromatography (HPLC) as described previously byGeschke

et al

. with some minor modifications [21]. Thelimit of detection for moclobemide and the three metab-olites was 5.0

m

g l

-

1

.The maximum plasma concentration (

C

max

) and thetime to

C

max

(

T

max

) were read directly from the plasmaconcentration–time curves if possible, otherwise an esti-mated

C

max

was used which was taken to be the first andhighest plasma concentration.

The terminal elimination half-lives for the parent drugwere derived from plasma concentration

vs.

time datausing a first-order elimination, one-compartment dispo-sition model. Data points prior to peak plasma concen-tration were ignored and an exponential decay was fittedto the plasma concentration–time data and half-life wascalculated. Half-lives for two of the three metaboliteswere also determined. Analysis and curve fitting wereperformed using GraphPad Prism version 3.02 for Win-dows (GraphPad Software, San Diego, CA, USA).

Statistical analysis

For descriptive statistics, means and standard deviations(SD) are quoted for normally distributed data, whilemedians and interquartile ranges (IQR) are used for non-parametric data. For comparison of two groups, unpaired

t

-test was used for normal populations and the Mann–Whitney test for nonparametric populations. For com-parison of proportions of two groups compared witheither control group, Fisher’s exact test was used. All

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statistical analysis was done using GraphPad InStat (ver-sion 3.02 for Windows 95; GraphPad Software).

Results

There were 127 admissions with moclobemide poisoningto HATS between January 1992 and June 2002. Twelvewere excluded because they ingested 600 mg or less.Only first admissions were included, so another nineadmissions were excluded, leaving 106 cases for analysis.Of these patients, 33 ingested moclobemide alone. Therewere 42 males and 64 females with a mean age of33 years (SD 12 years).

The clinical effects of all moclobemide poisonings aresummarized in Table 1. There were no deaths, compli-cations or major toxic effects in the moclobemide alonegroup despite a median ingested dose of 6 g (IQR 3.6–7.5 g; range 0.9–18 g). The patient who ingested 18 gdeveloped hyperreflexia, tachycardia and a temperatureof 37.4

∞

C, but no other significant effects.All major complications in the 106 patients, including

seizures and coma, occurred in patients taking coinges-tants and could be accounted for by the coingested drug(Table 2). The median dose of moclobemide in the 73patients coingesting other drugs was 4 g (IQR 2.3–6.7),which was significantly less than the moclobemide-aloneoverdoses (

P

=

0.028).The 33 cases of moclobemide-alone overdoses are

compared with the 21 cases where a serotonergic agent

was taken as a coingestant in Table 2. Eleven (52%) ofthe 21 patients coingesting a serotonergic drug developedserotonin toxicity, which was significantly more than formoclobemide alone overdoses, one of 33 (3%), [oddsratio (OR) 35, 95% confidence interval (CI) 4, 307;

P

<

0.0001]. In six of the 11 cases the features wereconsistent with severe serotonin toxicity necessitatingsedation and intubation of the patient. There was a sig-nificantly increased LOS for serotonergic coingestantoverdoses of 39 h (IQR 20–79 h)

vs.

moclobemide aloneoverdoses 12 h (IQR 9–20 h) and a significantlyincreased rate of ICU admission of 11 in 22 (52%)

vs.

one in 33 (3%) (OR 35, 95% CI 4, 307;

P

<

0.0001).The coingested agent in these 11 patients was an SSRIin five patients, venlafaxine in four patients, doxepin andtranylcypromine in one patient each. No patient ingestedmore than 30 defined daily doses (DDD) of the coinges-tant, one patient coingested only 150 mg of venlafaxineand another 750 mg of venlafaxine. The patient coingest-ing 150 mg venlafaxine developed severe serotonin tox-icity requiring intubation and paralysis (patient B).

Toxicokinetics

In five patients who developed significant serotonin tox-icity serial plasma concentrations of moclobemide andthree metabolites were measured and plotted as plasmaconcentration–time curves. Figure 2 shows the plasmaconcentration–time curves for the five patients. Informa-tion on coingestants taken in these five cases was based

Moclobemide aloneoverdoses (33)

Moclobemide overdoses with coingestants (73)

Baseline characteristics

Age (years) 27 (IQR 23–34) 34 (IQR 26–44)***Gender (% males) 8, 24% 34**,47%Dose (g) 6 (IQR 3.6–7.5) 4 (IQR 2.3–6.7)*Presentation time (h) 1.5 (IQR 1.0–3.3) 1.9 (IQR 0.8–4.0) NS

Clinical features

NeurologicalComa 0, 0% 4,

1

5.5%Seizures 0, 0% 6,

2

8.2%Cardiovascular

Tachycardia 7, 21% 15, 21%Arrhythmia 0, 0% 2,

3

3%Length of stay (median, IQR) 12 (9–20) 20 (13–38)***ICU admission 1, 3% 16,**** 22%Serotonin toxicity 1, 3% 13,

NS

18%

*

P

=

0.028; **

P

=

0.034; ***

P

<

0.01; ****

P

=

0.020. NS, Not significant;

1

, all four hadcoingested a tricyclic antidepressant;

2

, all had coingested proconvulsant drugs: dothiepin,doxepin, venlafaxine (3) and thioridazine;

3

, asystole occurred in one patient who coingestedmetoprolol and ventricular tachycardia occurred in another who coingested dothiepin.

Table 1

Clinical effects of 33 moclobemide overdose admissions where moclobemide was the only drug ingested (column A) compared with all other moclobemide overdose admissions where coingestants were taken.



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on the history, and was confirmed in each case by HPLC(Table 3).

The time to peak plasma concentration was delayed inat least two patients, occurring at 13 h in patient B and4.5 h in patient C. In patient B the delayed peak corre-sponded with a delayed onset of serotonin toxicity and ageneralized tonic clonic seizure 12 h after ingestion. Forthree of the patients the first plasma concentration wastaken after the peak.

A plot of

C

max

vs.

time is shown in Figure 3. Includedin the figure are data from pharmacokinetic studies anda linear regression of these data [22], as well as two otheroverdose cases where data were available [15].

C

max

appears to increase with increasing dose, but the pointsin our study fall below the expected values based on datafrom therapeutic doses (Figure 3).

The mean terminal elimination half-life for the fivepatients for the parent drug was 6.3 h (SD 2.5 h) and indi-vidual values are listed in Table 3. A plot of plasma elim-ination half-life

vs.

time shows that there is no significantcorrelation between dose and elimination half-life(Figure 3). The elimination of moclobemide was first orderin all cases with no evidence of dose-dependent kinetics.

Two of the metabolites with first-order eliminationalso had half-lives estimated (Table 3). Ro 12-5637, theN-oxide metabolite, had a similar terminal eliminationhalf-life to the parent drug, declining in parallel, suggest-ing that its kinetics was formation limited. In contrast,the plasma concentration curve of Ro 12-8095, the oxo-metabolite, declined with a longer half-life (Table 3),

which suggests that the metabolite was elimination lim-ited. Ro 16-3177 was found in very low concentrationsin the plasma, so no kinetic analysis was possible.

Discussion

Clinical effects of moclobemide poisoning

This study shows the spectrum of toxicity of moclobemidepoisoning when taken alone and when combined withserotonergic agents. Single-agent poisoning withmoclobemide causes minimal toxicity even when massiveamounts of drug are ingested. However, the combinationof moclobemide with other serotonergic drugs causesserotonin toxicity in over half of cases and severe serotonintoxicity in 29% of cases necessitating intubation, paralysisand sedation. The odds of developing serotonin toxicityin moclobemide plus a serotonergic drug overdose were35 times those of moclobemide-alone overdoses.

There was no evidence in this study to suggest thatthe serotonin toxicity occurring in the coingestant groupwas solely due to the overdose of the serotonergic agent(e.g. SSRI), and therefore, unrelated to the moclobemidepoisoning. The amounts of the serotonergic agentingested in patient who developed serotonin toxicitywere not massive (all

<

30 DDD), and in two patientswere therapeutic, one of which had severe serotonintoxicity. This is also supported by the fact that in SSRIoverdoses with no other serotonergic coingestants, sero-tonin toxicity only occurred in 15% and severe serotonin

Moclobemide aloneoverdoses (33)

Moclobemide overdoseswith

serotonergiccoingestants (21)

Moclobemide overdoseswith nonserotonergic

coingestants (52)

Baseline characteristicsAge (year) 27 (IQR 23–34) 30 (IQR 25–41)NS 36 (IQR 26–44)Gender (% male) 8, 24% 10, 48% 24, 46%Dose (g) 6 (IQR 3.6–7.5) 3 (IQR 1.7–7.9)NS 4.2 (IQR 2.7–6.3)Presentation time (h) 1.5 (IQR 1.0–3.3) 1.5 (IQR 1–3.9) NS 2 (IQR 0.8–3.9)Clinical featureSerotonin toxicity 1, 3% 11,* 52% 2, 4%Severe serotonin toxicity 0, 0% 6, 29% 0, 0%Features of serotonin toxicityClonus 0, 0% 11, 52% 2, 4%Hyperreflexia 5, 15% 12, 57% 7, 13%Rigidity 0, 0% 6, 29% 0, 0%Temp. >37.2 ∞C 0, 0% 8, 19% 1, 2%Temp. >38.5 ∞C 0, 0% 4, 14% 1, 2%Length of stay 12 (9–20) 39 (20–79)** 18 (12–26)ICU admission 1, 3% 12,* 55% 4, 8%

The third column contains all other overdoses where a nonserotonergic agent was taken.Comparison is between the first two columns only. NS, Not significant. *P < 0.01;**P < 0.0001.

Table 2 Comparison of serotonergic effects and complications between moclobemide alone overdoses and moclobemide overdoses where a serotonergic coingestant was taken.

G. K. Isbister et al.

446 © 2003 Blackwell Publishing Ltd Br J Clin Pharmacol, 56, 441–450

toxicity did not occur in 320 of our patients (unpublisheddata).

There continues to be disagreement over the defini-tion of serotonin toxicity [23–25], which appears to bea continuum of toxicity rather than a discrete syndrome[23, 25, 26]. This study provides some support for thishypothesis. There were patients with definite serotonin

toxicity who did not require any major interventions andwere often treated with oral cyproheptadine alone. How-ever, there was a group arbitrarily defined as severe sero-tonin toxicity, who had potentially life-threatening effectsand required major interventions in a critical care setting.

The specific treatment of serotonin toxicity is contin-ually evolving. There is increasing use of 5-HT2A receptor

Figure 2 Plasma concentration–time profile for moclobemide (�) (Ro 11-1163) and three of its metabolites, the N-oxide metabolite (Ro 12-5637 (�)), the oxo-metabolite (Ro 12-8095 (�)) and the ring-opened metabolite (Ro 16-3177 (�)) for five of the patients.

Patient A

0 1 2 3 4 50.001

0.01

0.1

1

10

100

Time (days)

mg/

L

0.001

0.01

0.1

1

10

100

mg/

L

0.001

0.01

0.1

1

10

100

mg/

L

0.001

0.01

0.1

1

10

100

mg/

L

0.001

0.01

0.1

1

10

100

mg/

L

Patient B

0 1 2 3 4 5

Time (days)

Patient C

0 1 2 3 4 5Time (days)

Patient D

0 1 2 3 4 5Time (days)

Patient E

0 1 2 3 4 5

Time (days)


© 2003 Blackwell Publishing Ltd Br J Clin Pharmacol, 56, 441–450 447

antagonists, such as cyproheptadine and chlorpromazine,which appear to be effective based on clinical experience[24, 27] and animal studies [28, 29]. However, all sixsevere cases in this series required intubation, sedation andmost importantly muscle paralysis. In the severe caseshypertonia and clonus caused both respiratory compro-mise due to chest wall rigidity and increased muscle activ-ity contributing to hyperthermia. In severe cases thismuscle activity can result in rhabdomyolysis [9]. Patients

coingesting moclobemide and another serotonergic agentmust be managed aggressively in a critical care area to pre-vent severe serotonin toxicity. 5-HT2A receptor antagonistsmay reverse these effects in isolated cases [24, 27, 30] andmay be useful if administered early in the course of theoverdose, but there remain no controlled trials to supportthe use of these agents. However, in severe cases sup-portive care must take priority to prevent life-threateningcomplications. A rapidly rising temperature, muscle rigid-ity and ventilatory failure, with a rising pCO2, are indi-cators of life-threatening serotonin toxicity and patientswith these signs should be intubated and paralysed.

Plasma moclobemide drug concentrations were onlydetermined for five patients in this study. Although thisis the best way to confirm ingestion of the drug, it wasnot possible for all patients. However, all overdosepatients admitted to HATS have the drug ingested con-firmed by history from the patient, and this is confirmedwith collateral history from family, friends and ambulanceofficers, as well as evidence of empty drug containers.Previous studies of overdose have demonstrated that thiscorresponds to definite ingestion in the majority of cases[31, 32].

Toxicokinetics of moclobemide

The kinetics of drugs in overdose is a far less precisescience than the kinetics of drugs at therapeutic dosesbecause it is opportunistic, rather than planned. There areinaccuracies in the time of the ingestion, the stated doseand often the first plasma sample is not collected until1–4 h after ingestion. In addition, the patient often spon-taneously vomits or receives decontamination with acti-vated charcoal, which decreases the ingested dose by anunknown amount. This means that the absorption phaseof the plasma concentration–time graph is either missingor incomplete and it is usually difficult or impossibleaccurately to estimate the AUC, Tmax or Cmax.

After a single therapeutic dose moclobemide is rapidlyand completely absorbed with a Tmax of 1–1.5 h [22]. Inonly two of our patients was it possible to estimate the

Table 3 Toxicokinetic information on five patients where serial plasma concentrations were measured.

Patient A B C D E

Estimated dose (g) 6 12 9 3 1.8Coingested drugs Venlafaxine Venlafaxine Fluvoxamine Sertraline, amitriptyline CitalopramCmax (mg l–1) 28 50 30 8 25Terminal half-life (h) 10.2 7.5 4.7 4.3 4.9MetabolitesRo 12-5637 half-life (h) 8.6 6.8 6.5 4.3 4.6Ro 12-8095 half-life (h) 10.9 10.3 –1 4.3 6.2

Information on Ro 16-3177 not included. 1, Too few points for analysis.

Figure 3 Maximum concentration (Cmax) vs. estimated dose plot (top) and plasma elimination half-life vs. dose (bottom). PK data are taken from Mayersohn et al. [22] and the other overdose data are from Hackett et al. [15]. Patient A had gastric lavage and activated charcoal approximately 4 h after ingestion. Patient B who took 12 g was given activated charcoal 75 min after ingestion and patient C who took 9 g spontaneously vomited some tablet material within 60 min. In patients D and E, the Cmax may be a significant underestimate, so has been marked with an open box. The drug ingestion history for patient D taking 3 g was very unreliable. Cmax (�); estimated Cmax (�); PK Data (�); and other overdoses (�).

0 3 6 9 12 150

50

100

150

Dose (g)

Cm

ax (

mg/

L)

0 3 6 9 12 150

5

10

15

Dose (g)

Elim

inat

ion

half-

life (

hour

s)



Tmax, and in both cases it exceeded 1.5 h. A prolongedabsorption phase may occur following overdose for avariety of reasons, including delayed gastric emptying,formation of tablet aggregates and saturation of the usualmechanisms of absorption, due to the excessive amountof drug in the gastrointestinal tract.

Moclobemide has an oral bioavailability ranging from43% to 59% because of significant variable first-passmetabolism [33], which further increases to 86% withmultiple therapeutic doses, due to either saturation orautoinhibition [33]. Peak concentration (Cmax) increaseslinearly with dose (although there is substantial interin-dividual difference [22]), and almost doubles at steadystate after 10 days of multiple doses [34].

An apparent Cmax in our cases was estimated from eitherthe actual peak concentration (available in two patients)or the first plasma concentration in the other threepatients. The Cmax appears to increase slightly with dose,but falls below those predicted from the kinetics derivedafter therapeutic dose (Figure 3). This may be explainedpartly by the fact that the patients A, B and C eitherspontaneously vomited or were decontaminated early.

Following oral administration of 50 mg, a mean of95% of a dose of moclobemide is excreted in urinewithin 96 h [35]. The parent drug is almost completelymetabolized, with at most 0.4% excreted unchanged.There are at least 19 metabolites accounting for 64% ofthe dose [35]. There are two major metabolic cascades,morpholine C-oxidation and morpholine N-oxidation(Figure 1). Morpholine C-oxidation is the most impor-tant metabolic pathway producing the major plasmametabolite, Ro 12-8095, which is detectable in plasmain amounts equivalent to the parent drug. It undergoesextensive metabolism and is not detectable in urine(Figure 1) [21, 35, 36]. It has no inhibitory activity onMAO-A. The second important pathway is N-oxidationproducing the other major metabolite detectable inplasma, Ro 12-5637 (M5) (Figure 1). It has some MAO-A inhibitory activity, but occurs in plasma at much lowerconcentrations than the parent compound. It is detect-able in trace amounts in urine. Aromatic hydroxylationand deamination also occur but are quantitatively lessimportant pathways (Figure 1).

The involvement of the different families of cyto-chrome P450 enzymes in the metabolism of moclobe-mide is unresolved. Gram et al. demonstrated that theformation of the Ro 12-8095 by C-oxidation was mainlydue to the cytochrome P450 2C19 enzyme [37]. In poormetabolizers (PM) of mephenytoin (2C19 phenotype)the elimination half-life of moclobemide was prolongedat 4 h and the plasma concentration decline of Ro 12-8095 was in parallel (i.e. formation-limited kinetics). Inextensive metabolizers (EM), the mean half-life ofmoclobemide was 1.8 h, and the decline of Ro 12-8095

was longer than the parent, indicating elimination-limited kinetics of the metabolite [37]. At steady state thedifference remained and earlier observations [36] wereconfirmed that moclobemide had nonlinear kinetics,with a reduced clearance at steady state [37].

In the five overdose patients the pattern of eliminationof moclobemide and its metabolites was almost identicalto the elimination of moclobemide seen in EM ofmephenytoin at steady state [37], with formation-limitedelimination of Ro 12-5637, but not Ro 12-8095, andthe relatively similar concentrations of the parent and Ro12-8095. Thus, all five patients are likely to be EM ofmephenytoin (2C19) [38] and genetic polymorphism ofP450 2C19 is unlikely to explain the increased terminalelimination half-lives.

The apparent oral clearance of moclobemide variessignificantly between individuals, as expected for a drugwith intermediate to high hepatic extraction [22], butdecreases overall with increasing dose. This has beenattributed to high first-pass metabolism which appears tosaturate [22]. Clearance is also reduced at steady state,suggesting that moclobemide may reduce its own metab-olism [22]. However, the plasma concentration–timecurves remain log-linear before and after multiple doseadministration, indicating that there is inhibition ofmetabolism (possibly metabolite inhibition), rather thanoverall saturation of metabolism [22, 34, 36, 39].

Moclobemide has an elimination half-life of 1.6–2.1 hin healthy volunteers [2, 33, 36, 39], which does notincrease with age or renal impairment. The half-life isprolonged in patients with hepatic cirrhosis [33], andprolonged with multiple doses. A terminal plasma elim-ination half-life was estimated in all five of our patients,but there was no relationship between dose and plasmaelimination half-life (Figure 3). The plasma concentra-tion–time curves in our five patients were similar to thosefrom single-dose and multiple-dose pharmacokineticsstudies, with first-order elimination and no evidence ofsaturation [21, 34, 39]. Our study thus provides evidencethat overall moclobemide metabolism and elimination isnot saturable, even with extreme doses and very highplasma concentrations.

There are only two previous studies on the toxicoki-netics of moclobemide [9, 15]. The first by Hackett et al.reported two patients with delayed absorption and pro-longed elimination half-lives [15]. The elimination half-lives in these patients were 5.6 h and 12.5 h. Both hadbeen taking the drug therapeutically for months, whichmay partly explain the increase in half-life, but theauthors were not able to account for the much longerhalf-life in one patient [15]. In a later case report, Poweret al. described a fatal case where the initial eliminationhalf-life was about 5 h [9]. However, the elimination ofmoclobemide was significantly compromised about 30 h


© 2003 Blackwell Publishing Ltd Br J Clin Pharmacol, 56, 441–450 449

after ingestion due to multiorgan failure and most prob-ably a dramatic reduction in hepatic clearance [9]. Theestimated terminal elimination half-lives in these studiesare consistent with the prolonged half-lives determinedin our study.

Patients C, D, and E had plasma elimination half-livesthat were about twice that predicted from a single ther-apeutic dose. None was taking moclobemide therapeuti-cally, so the increased half-lives were not a result ofmultiple dosing. All three coingested antidepressants(Table 3), but this is unlikely to account for the longerhalf-lives because only fluvoxamine is a potent inhibitorof 2C19 [40, 41].

Patient A and B, who both coingested venlafaxine, hadplasma elimination half-lives more than twice that of theother three patients. There is no evidence that venlafax-ine or its metabolites inhibit 2C19 [40], so this is unlikelyto account for the prolonged plasma elimination half-lifein these two patients. Neither was unwell or had ahistory of renal or hepatic disease. It is thus likely thatthe explanation for their prolonged terminal eliminationhalf-lives in patients A and B is unrelated to venlafaxine.Interindividual differences in clearance between the fivepatients may be the only reason for the large variationin half-lives in overdose, which is consistent with thelarge interindividual clearance seen with therapeuticdoses [22].

The prolonged absorption and elimination of moclobe-mide is consistent with the time course of the clinicaleffects, when they were apparent. In patients with sero-tonin toxicity the median length of stay was >36 h atwhich time there were still significant plasma concentra-tions of moclobemide. The major plasma metabolite Ro12-8095 was inactive, and the plasma concentration of theonly active metabolites, Ro 12-5637 and Ro 16-3177were much lower in the five patients. Thus, the effects ofmoclobemide in overdose would be expected to correlatemainly with plasma concentrations of the parent drug.

Although this study suffers from being a retrospectivereview of a clinical database, the information in thedatabase had been entered prospectively in a standardizedblinded manner [17, 18]. The routine collection of allcases allows a better characterization of the full spectrumof effects and the importance of coingestants. A furtherproblem with the study was the use of Sternbach’s cri-teria to define serotonin toxicity. The use of the clinicaltoxicologist’s diagnosis of serotonin toxicity was added toimprove the definition, but improved objective criteriaare needed to clarify this diagnosis.

Conclusions

This study is the first to attempt to characterize morefully the toxicokinetics of acute overdose with moclobe-

mide. It illustrates the difficulties in obtaining data, theinaccuracies of the data and the estimates that need tobe made. We have shown that in overdose both theabsorption and the terminal elimination half-life ofmoclobemide are prolonged. There is no evidence ofsaturation of hepatic metabolism, and the reason for thereduced elimination is not clear. The time course ofoverdose is much longer than that predicted by therapeu-tic dose pharmacokinetic studies.

Major toxicity associated with moclobemide occurredonly in the presence of coingestion of a serotonergicdrug, and the effect appeared to be an interactionbetween the serotonergic coingestant and moclobemide,rather than attributable to the toxicity of the coingestantalone. The effects of moclobemide-alone overdose areminor, even with massive ingestions, and do not need tobe managed in an ICU or require prolonged monitoring.

We would like to thank Stuart Allen for extracting the data fromthe database, and Deb Whyte and Toni Nash for entering the datainto the database.

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Moclobemide poisoning: toxicokinetics and occurrence of serotonin toxicity

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