DRUG DISPOSITION

Clin . Pharmacokinet. 20 (6): 447-462. 1991

0312-5963/ 91 /0006-0447/$08.00/0
© Adis International Limited. All rights reserved.
CPK1022A

Clinical Pharmacokinetics of Clomipramine

Androniki E. Balant-Gorgia, Marianne Gex-Fabry and Luc P. Balant
Therapeutic Drug Monitoring and Clinical Research Unit, Psychiatric University
Institutions of Geneva, Geneva, Switzerland

Contents
447 Summary
448 I. Classification of Tricyclic Antidepressants
44 1.1 Chemical Structure
44 1.2 Pharmacological Profile
449 1.3 Sedative and Clinical Properties
449 2. Analytical Methods
449 3. Biopharmaceutics
449 4. Basic Pharmacokinetic Profile: the Fingerprint
452 4. 1 Gastrointestinal Absorption
452 4.2 Distribution and Protein Binding
452 4.3 Metabolism
453 4.4 Genetic Polymorphism of Hydroxylation
453 4.5 Interethnic Differences in Clomipramine Metabolism
454 4.6 Pharmacokinetics in Normal Conditions After a Single Dose
454 4.7 Indications for Nonlinear Pharmacokinetics
455 5. Pharmacokinetics Under Steady-State Conditions
455 5.1 Effect of Age
455 5.2 Pharmacokinetic Drug-Drug Interactions
456 5.3 Environmental Factors
456 6. Clomipramine Blood Concentrations and Clinical Response
459 7. Blood Concentration Monitoring
459 8. Conclusions

Summary Clomipramine is a tricyclic antidepressant medication widely used in Western Europe. Its
pharmacokinetics have been studied essentially in healthy volunteers. By combining published
information obtained during observational studies, it has been possible to derive a fairly precise
picture of the behaviour of both parent compound and main metabolite (demethyl-c1omipramine)
in humans.
Clomipramine can be compared with amitriptyline or imipramine so far as its physicochem-
ical properties are concerned. As a consequence, its pharmacokinetic profile is also similar to
that observed for these 2 drugs. Clomipramine is well absorbed from the gastrointestinal tract,
but undergoes an important first-pass metabolism to demethyl-c1omipramine which is pharma-
cologically active and participates in both therapeutic and unwanted effects. Protein binding is
high, and the apparent volume of distribution is very large (i.e. > IOOOL). After reaching the
systemic circulation, clomipramine is further biotransformed into demethyl-c1omipramine, and
448 Clin. Pharmacokinet. 20 (6) 1991

both active principles are hydroxylated to metabolites which are further conjugated before being
excreted in urine. Hydroxylation of parent drug and metabolite is under polymorphic genetic
control by the same cytochrome P450 as debrisoquine and sparteine. The apparent elimination
half-life of clomipramine is about 24h and that of demethyl-c1omipramine, 96h. Accordingly, the
time to reach steady-state for both active moieties is in general around 3 weeks.
Various pathological or environmental factors influence the behaviour of clomipramine and
demethyl-c1omipramine. Patients genetically deficient in hydroxylation accumulate demethyl-
clomipramine at high concentrations that can produce serious side effects and/or nonresponse.
The same is true for the coadministration of neuroleptics, in particular phenothiazines. Smoking
induces demethylation, whereas long term alcohol intake appears to reduce this metabolic path-
way. Finally, age usually diminishes both demethylation and hydroxylation, leading to a lower
daily dose of clomipramine in most elderly patients.
Studies relating blood concentrations of clomipramine and demethyl-c1omipramine are con-
flicting. However, analysis of the available information indicates that blood concentrations lower
than 150 /ig/L are usually associated with nonresponse, whereas those above 450 /ig/L seldom
lead to an improvement in the efficacy of therapy. As a consequence clomipramine, like the other
tricyclics, is an antidepressant with a fairly narrow therapeutic range. This property, combined
with a high interindividual variability, makes this class of drugs ideal candidates for blood con-
centration monitoring.

1. Classification of Tricyclic to be found on the side-chain, some compounds

Antidepressants
Clomipramine (Anafranil®) has been available
for many years and in a number of countries for
the treatment of depression, and it is one of the
most widely used tricyclic antidepressants in West-
ern Europe. In some other countries, e.g. the US,
it has only recently been approved for the treat-
ment of particular conditions such as obsessive
compulsive disorders (McTavish & Benfield 1990).
This is probably the reason for its pharmacokin-
etics having been less well documented with for-
mal studies than those of other tricyclic antidepres-
sants such as imipramine and desipramine (Sallee
& Pollock 1990). However, thanks to the wide-
spread use of the drug, a good deal of information
has become available during observational studies.
Thus, combining the information available in the
literature, it is possible to derive quite a precise
picture of the behaviour of both parent compound
and main metabolites in healthy volunteers and
patients.
1.1 Chemical Structure
All the tricyclic antidepressants have basically a
very similar chemical structure. From a phar-
macokinetic point of view, the major difference is
being N-dimethylated (e.g. imipramine) while others
are N-monomethylated (e.g. desipramine). This
difference is, however, merely arbitrary, since the
dimethylated drugs are metabolised to the mono-
methylated ones. Thus, for example, the steady-
state concentrations of clomipramine are usually
2.5 times lower than those of demethyl-clomipra-
mine. Accordingly, the administration of clomi-
pramine leads to a therapeutic effect by both di-
methylated and monomethylated substances. This
is not without consequences since, as described
below, their pharmacological profiles are not iden-
tical.
1.2 Pharmacological Profile
It is possible to classify the antidepressant agents
according to their potency in inhibiting the recap-
ture of neurotransmitters. Table I demonstrates this
classification in the case of noradrenaline (norepi-
nephrine) and serotonin.
According to this classification, clomipramine
may be considered to be the most serotoninergic
compound among the drugs listed in table I; but
since steady-state concentrations of demethyl-
clomipramine are usually 2.5 times higher than
Clinical Pharmacokinetics of Clomipramine
those of the parent compound, it is not evident
that this classification has any 'l?;reat clinical rele-
vance.
1.3 Sedative and Clinical Properties
A useful parameter for the choice of an anti-
depressant is its sedative potential. The ascending
order for the sedative potential of the common tri-
cyclics is: desipramine < nortriptyline < imipra-
mine < clomipramine < amitriptyline.
It is difficult, if not impossible, to rank the dif-
ferent tricyclic antidepressant compounds in terms
of their clinical efficacy since in all well designed,
double-blind, comparative clinical trials they show
identical profiles. It is thus possible to state that
clomipramine has an efficacy (and side effect) pro-
file in line with those of other tricyclic antidepres-
sants. Its wide use in some countries and not in
others is thus representative of the local, and often
historical, reasons that determine the choice of one
compound over others. It is nevertheless interest-
ing to note that in many clinical trials for the study
of potentially interesting new antidepressants,
clomipramine has been used as the reference, at
least in Europe.
Table I. Rank order of tricyclic antidepressants by potency in
inhibiting the recapture of noradrenaline (norepinephrine) [NA)
and serolonin (5-HT)
Parent compound Metabolite NA 5-HT
Lofepramine a Desipramine ++ +
Desipramine +++ + the Fingerprint
Imipramine Desipramine +++ ++
Amitriptyline Nortriptyline ++ ++
Nortriptyline + +
Clomipramine Demethyl- ++ +++
clomipramine b
a Considered an inactive prod rug of desipramine, but could
nevertheless play a certain role in the side effect profile of
the drug.
b Not manufactured as such. Demethyl-clomipramine has been
shown to be a stronger inhibitor of NA uptake, and a weaker
inhibitor or 5-HT uptake, than the parent compound.
Key: + = low potency; ++ = medium potency; +++ = high
potency.
449
2. Analytical Methods
A number of analytical methods have been de-
vised to measure clomipramine and de methyl-
clomipramine in biological fluids (Scoggins et al.
1980; Norman & Maguire 1985). Among the 'non-
classical' methods Carnis et al. (1976) have devel-
oped a double radioisotope derivatisation assay
specific for both, and Read et al. (1977) have de-
scribed a radioimmunoassay which, although suf-
ficiently sensitive and specific to monitor plasma
clomipramine concentrations, suffers from the fact
that it does not permit simultaneous determination
of the metabolite. However, the most commonly
used techniques are based on separations by gas or
liquid chromatography, as shown in table II. Some
of these methods are specific for 1 or 2 drugs. Other
methods are capable of determining many anti-
depressants and are useful for therapeutic concen-
tration monitoring since most psychiatric care units
use several antidepressants (Volin 1981).
3. Biopharmaceutics
Clomipramine (Anafranil®) is available as 10
and 25mg tablets, 75mg slow release tablets and an
injectable solution. No published data are avail-
able on the performance of the slow release form-
ulation.
4. Basic Pharmacokinetic Profile:
In order to compare the pharmacokinetics of a
drug in different subpopulations (e.g. health and
disease), it is necessary to compare the basic phar-
macokinetic parameters with those obtained under
standardised conditions (i.e. in formal studies with
healthy volunteers). The parameters usually nec-
essary to define this basic profile are systemic
availability (F), clearance (CL) and volume of dis-
tribution (Vd) [Balant et al. 19901. Due to the
structural and physicochemical similarities be-
tween clomipramine and the other tricyclic anti-
450 Clin. Pharmacokinet. 20 (6) 1991

Table II. Analytical methods for clomipramine and its metabolites in biological fluids

Biological fluid Detection Species Special conditions a/ Comments Reference

measured mobile phase b

Gas chromatography (GC)

Plasma N C Gifford et al. (1975)
Whole blood MS C,DC Deuterium labelled Dubois et al. (1976)
internal standards
Plasma MS C, DC Alfredsson et al.
(1977)
Plasma FI C, DC Broadhurst et al.
(1977)
Plasma or serum FI C,DC Measures also imipramine, Nyberg & Martensson
desipramine, amitriptyline, (1977)
nortriptyline, trimipramine
and protriptyline
Plasma N C,DC Measures also imipramine, Dawling & Braithwaite
desipramine, amitriptyline, (1978)
nortriptyline and maprotiline
Plasma N C,DC Derivation with Measures also imipramine, Rovei et al. (1980)
heptyfluorobutyric desipramine, amitriptyline,
anhydride nortriptyline, maprotiline and
cyclobenzaprine
Plasma N C, DC Measures also imipramine, Bredesen et al. (1981)
desipramine, amitriptyline,
nortriptyline, doxepin,
demethyl-doxepin,
trimipramine, demethyl-
trimipramine and dibenzepin
Plasma TI C, DC Capillary column Measures about 10 Gupta et al. (1983)
antidepressant drugs and
their de methylated
metabolites
Plasma N C, DC Derivatisation with Measures also Ninci & Sgaragli
trifluoroacetic chlorpromazine and the 2 (1986)
anhydride N-demethyl metabolites
Whole blood or MS C, DC Capillary column and Sioufi et al. (1988)
plasma derivatisation with
pentafluoropropionic
anhydride
Whole blood or N C,DC Measures also imipramine, Balant-Gorgia et al.
plasma desipramine, amitriptyline, (1989b)
and nortriptyline

High performance liquid chromatography (HPLC)

Plasma C, DC Ion pair partition Lagerstrom et al.
chromatography (1976)
Plasma UV C,DC Butanol/hexane Mellstrom & Eksborg
(1976)
Plasma or whole UV C, DC Ammonium hydroxide Measures also amitriptyline, Moyes & Moyes
blood in methanol nortriptyline and protriptyline (1977)
Clinical Pharmacokinetics of Clomipramine 451

Table II. Contd

Biological Iluid Detection Species Special conditions a / Comments Relerence

measured mobile phase b

Plasma UV C.DC Hexane/ Westen berg et al.

dichloromethane/ (1977a , b)
methanol

Plasma UV C,DC Butanol/hexane Measures also imipramine, Melstrom & Tybring

desipramine, amitriptyline (1977)
and nortriptyline
Serum UV C,DC Dichloromethane/ Measures also imipramine, Uges & Bouma (1979)
methanol/acetic acid/ desipramine, amitriptyline,
diethylamine nortriptyline, doxepin,
maprotiline, protriptyline and
trimipramine
Plasma UV C,DC Ammonium hydroxide Measures also imipramine, Moyes & Moyes
in methanol desipramine, amitriptyline (1980)
and nortriptyline
Plasma or whole UV C,DC Ethanol/hexane/ Measures also imipramine, Godbillon & Gauron
blood dichloromethane/ desipramine and hydroxy- (1981)
diethylamine imipramine
Plasma UV C,DC Diethylamine/water/ Diquet et al. (1982)
acetonitrile/ethanol
Plasma UV C,DC Acetonitrile/ Measures also imipramine, Lagerstrom et al.
octylamine/ amitriptyline, nortriptyline and (1983)
dimethyloctylamine/ trimipramine
trimethyloctyl
ammonium/
phosphoriC buffer
Serum UV C, DC Ammonium hydroxide Measures about 8 Sutfin et al (1984)
in methanol antidepressants and their
main metabolites
Plasma UV C, DC Acetonitrile/methanol/ Measures about 10 Visser et al. (1984)
phosphate buffer antidepressants and their
main metabolites
Plasma, whole EC C,DC Acetate buffer in Derived from an imipramine Balant-Gorgia et al.
blood or urine acetonitrile method by Suckow & (1986)
Cooper (1981). Measures
also the hydroxylated
metabolites of clomipramine.
Can be adapted for other
compounds
Plasma or urine EC C, DC Phosphate buffer with Measures also 4 Spreux-Varoquaux et
tetramethylammonium hydroxylated metabolites of al. (1987)
chloride/acetonitrile clomipramine and di-
demethyl-clomipramine

a For GC.
b For HPLC.
Abbreviations: N = nitrogen; MS = mass spectrometry; FI = flame ionisation; TI = thermioniC; UV = ultraviolet; EC = electrochemical;
C = clomipramine; DC = demethyl-c.:lomipramine.
452 Clin. Pharmacokinet. 20 (6) 1991

depressants, its 'fingerprint' is close to that defined
for the other compounds.
4.1 Gastrointestinal Absorption
Clomipramine is well absorbed from the gas-
trointestinal tract, but as with many lipophilic drugs
its hepatic extraction coefficient is important.
Accordingly, hepatic first-pass metabolism to
demethyl-clomipramine reaches up to 50% (Evans
et al. 1980). This represents an important source
of interindividual variability in blood concentra-
tions of the drug and its metabolite.
4.2 Distribution and Protein Binding
Protein binding of clomipramine and demethyl-
clomipramine is high; the respective free fractions
(fu) at therapeutic concentrations are 2.2% (range
1.4 to 3.5%) and 3.6% (range 2.3 to 6.3%) as meas-
ured at steady-state in a group of patients (Mar-
tensson et al. 1984). From the same data it can be
hypothesised that both compounds have a com-
mon binding site on plasma proteins and that (\!I-
acid glycoprotein plays an important role in the
binding of these 2 substances.
The high Vd of clomipramine (i.e. more than
lOOOL; see table III) is in good agreement with its
physicochemical properties. The binding similari-
ties of demethyl-clomipramine and clomipramine,
as well as the lipophilicity of the 2 compounds,
allow us to predict that demethyl-clomipramine will
also have a Vd in the same order of magnitude.
This factor is important in overdose situations,
since it accounts for the ineffectiveness of haemo-
perfusion and haemodialysis as with the other tri-
cyclic antidepressants (Sallee & Pollock 1990). The
lipophilicity of clomipramine is also responsible for
its passage in maternal milk at concentrations sim-
ilar to those in plasma (Takemura et al. 1982).
4.3 Metabolism
One major route of biotransformation of clom-
ipramine is demethylation at the nitrogen of the
N-dimethylamino group. Other metabolites are
present in plasma and/or urine and comprise
hydroxylated and conjugated derivatives. Urinary
and faecal recovery after an oral dose of
[14C]clomipramine is more than 90% (Faigle &
Dieterle 1973), essentially as metabolites. In ad-
dition to demethyl-clomipramine among the de-
scribed metabolites in plasma, 8-hydroxy-clomi-
pramine and 8-hydroxy-demethyl-clomipramine
have been investigated. Their concentration at
steady-state is about 40 to 50% of that of the non-

Table III. Mean (± SO) pharmacokinetic parameters of clomipramine under normal conditions

No. of Dosel Assay tV2 (C) tV2 (DC) CL(C) Vd (C) F (C) Reference
subjects route [hi [hi [L/h/k91 [L/kgl

10a 150mgtpO GC 22-84 Not calculated Dawling et al.

(1980)

9 50mg/PO GC-MS 20.4 ± 6.1 36.5 ± 13.2 0.48 Evans et al.

50mg/ 17.7 ± 2.6 0.65 ± 0.15 16.6 ± 4.9 0.36-0.68 (1980)
2h inf

15 1 mg/kg GC-N 26 ± 8.9 Not detected b Ollagnier et al.

3h inf (1984)

a Depressed patients aged between 21 and 78 years (mean 51 years). which may explain the rather large variability in half-lives.
b Detection limit too low.
Abbreviations: tV2 = elimination half-life; CL = clearance; Vd = apparent volume of distribution; F = bioavailability; PO = oral;
inf = intravenous infusion; GC =gas chromatography; GC-MS = gas chromatography-mass spectrometry; GC-N =gas chromatography-
=
nitrogen detection; C clomipramine; DC = demethyl-clomipramine.
Clinical Pharmacokinetics of Clomipramine
hydroxylated compound (Balant-Gorgia et al. 1986;
Linnoila et al. 1982). The 4 compounds show ef-
fective in vitro inhibition of serotonin uptake into
platelets. The role of the hydroxylated metabolites,
however, is not defined since their distribution into
brain tissue is not known. Accordingly, blood con-
centration monitoring is usually limited to clomi-
pramine and demethyl-c1omipramine.
After oral administration of radiolabelled clom-
ipramine, up to 60% of the dose may be detected
in urine, the major proportion of this consisting of
a mixture of hydrophilic, polar metabolites, rather
than unchanged drug or demethyl-c1omipramine
(Faigle & Dieterle 1973). These polar compounds
are essentially the hydroxy derivatives of clomi-
pramine and demethyl-c1omipramine and their
glucuro and sulfate conjugates.
The demethyl metabolites of imipramine (i.e.
desipramine) and amitriptyline (i.e. nortriptyline)
have been marketed in their own right. Accord-
ingly, pharmacokinetic studies have been per-
formed with the metabolites, and their behaviour
in humans is thus well known. This is not the case
for demethyl-c1omipramine, which has been in-
vestigated only after administration of the parent
compound.
4.4 Genetic Polymorphism of Hydroxylation
The hydroxylation of clomipramine and de-
methyl-clomipramine is under genetic control sim-
ilar to that of debrisoquine and sparteine (Balant-
Gorgia et al. 1986). This may lead in poor meta-
bolisers of debrisoquine to very high concentra-
tions of demethyl-c1omipramine, whereas those of
clomipramine are less influenced (Balant-Gorgia et
al. 1989b; Gex-Fabry et al. 1990). In some patients,
concentrations may reach the subtoxic level de-
spite the administration of doses considered as
normal in other patients (i.e. 100 to 150 mg/day).
In fact, tricyclic antidepressants are among the few
drugs for which genetic polymorphism has been
shown to be highly relevant in the clinical situation
(Brosen & Gram 1989). The combined facts that
some patients fail to respond to high concentra-
tions of tricyclic antidepressants and about 5 to 10%
453
of Caucasian populations show defective hydroxy-
lation are probably important at 2 levels: (a) when
individual patients are treated in settings without
drug monitoring facilities, since a lack of response
may induce the clinician to further raise the daily
dose of medication; and (b) in double-blind clinical
trials, in which nonresponse may be the conse-
quence of unwanted high concentrations of the ac-
tive compound. This fact should encourage the
practice of taking blood samples during phase III
or phase IV clinical trials in order to detect patients
with abnormal responses for pharmacokinetic rea-
sons. In addition, the use of appropriate popula-
tion approaches (Gex-Fabry et al. 1990) may help
discover 'abnormal' subpopulations at an early stage
of drug development (Balant et al. 1989).
4.5 Interethnic Differences in
Clomipramine Metabolism
In this respect it is interesting to note that as
early as 1977, Allen et al. administered clomipra-
mine to English and Asian volunteers. It was found
that plasma concentrations of clomipramine in
Asian subjects were higher than in their English
counterparts. The authors concluded that the man-
ner in which clomipramine is handled in the body
is dependent on ethnic origin. However, Luscombe
(1979) noted that 'this conclusion should be viewed
with reservation since plasma concentrations in
Asian volunteers were of the same order as other
workers have found in European subjects' [Jones
& Luscombe (1976) in the United Kingdom;
Alfredsson et al. (1977) in Sweden; Westenberg et
al. (l977a) in the Netherlands]. Ten years later it
is possible to discuss these observations taking into
account recent findings in pharmacogenetics (Ber-
tilsson 1990). There are pronounced interethnic
differences in the incidence of poor metabolisers
of debrisoquine/sparteine: the figure is 5 to 10% in
Caucasians, but only about 1% of Orientals (Chinese
and Japanese) have a metabolic ratio above 12.6,
i.e. the anti mode established in Caucasians. It was
shown, however, that Chinese subjects with a poor
metaboliser genotype for debrisoquine may express
it as a phenotype close to extensive metaboliser
454
Caucasians (Bertilsson 1990). In the absence of
studies conducted to test the potential influence of
these differences on clomipramine disposition it is
difficult to decide if the observations of Allen et
al. (1977) were artifactual or not. However, since
defective hydroxylation influences essentially de-
methyl-clomipramine concentrations and only
marginally those of clomipramine, it is evident that
the comparison of only clomipramine concentra-
tions hinders any interpretation of the data avail-
able at the time.
This example shows the importance of recog-
nising not only the existence of interethnic differ-
ences in genetic polymorph isms at the genetic level,
and their influence on the metabolism of probe
drugs such as debrisoquine, but also the necessity
of testing the clinical relevance of such findings us-
ing the drug itself in the target populations. This
is particularly important if drugs developed in the
West, and which have been tested mostly in Cau-
casians, are to be used with different daily doses
in other ethnic groups such as Orientals. Naturally,
the converse is true for drugs developed, for ex-
ample, in Japan (Balant et al. 1990).
4.6 Pharmacokinetics in Normal Conditions
After a Single Dose
The pharmacokinetic profiles of clomipramine
and demethyl-c1omipramine have been studied after
oral and intravenous administration to healthy
volunteers and depressed patients (table III).
The only comprehensive study published (Ev-
ans et al. 1980) permits some additional com-
ments. Table IV indicates some comparisons be-
tween clomipramine and its metabolite given by
both routes of administration. As expected for a
classical tricyclic antidepressant, the Vd is high (""
lIOOL), as is the plasma CL ("" 45 L/h). After intra-
venous administration the peak plasma drug con-
centration (C max ) for demethyl-c1omipramine is
only 4% of that for clomipramine, whereas this fig-
ure is about 18% after oral administration, due to
first-pass metabolism. The same type of observa-
tion is valid for the ratios of the areas under the
concentration-time curves (AUC) after oral and
Clin. Pharmacokinet. 20 (6) 1991
intravenous administration: if the absolute bio-
availability of the drug were calculated on the basis
of the demethyl-c1omipramine concentrations a
value of 1.3 would result, whereas in reality this
value is about 0.5 if clomipramine concentrations
are considered. This is a good example of the dif-
ficulties encountered in the interpretation of me-
tabolite data during bioavailability studies. In the
case of clomipramine both compounds contribute
to the therapeutic activity and, accordingly, neither
figure unequivocally indicates the amount of ac-
tive principle reaching the general circulation and
(ultimately) the site of action. This situation is even
more complicated if the clinical relevance of such
findings is to be discussed, since as noted above,
under normal conditions at steady-state, the con-
centrations of demethyl-c1omipramine are about 2.5
times higher than those of the parent compound.
The mean (± SO) half-life of demethyl-c1omi-
pramine calculated by Evans et al. (1980) is 36.5
± 13.2h. It is, however, questionable if this is the
true value, since it has been shown that steady-
state concentrations of clomipramine are usually
reached after 1 or 2 weeks' treatment at a constant
daily dose, but that demethyl-c1omipramine con-
centrations are still rising until 3 to 4 weeks of a
constant dosage regimen have elapsed. It is thus
not quite clear if some form of concentration and/
or time dependence operates for demethyl-c1omi-
pramine. It has even been reported that in some
(rare) patients steady-state cannot be reached (Burch
et al. 1982; Hullin 1980).
4.7 Indications for Nonlinear
Pharmacokinetics
One case report shows a clear nonlinear de-
crease of blood demethyl-c1omipramine concentra-
tions in a patient phenot ped as a poor metaboliser
of debrisoquine (Balant-Gorgia et al. 1987). In a
prospective study in depressed patients receiving
clomipramine 75 or 150mg as an infusion or as
oral tablets, it was found that the CL of clomipra-
mine might be concentration dependent, and
doubling the dose led to steady-state concentra-
tions 3 and 4 times higher for clomipramine and
Clinical Pharmacokinetics of Clomipramine
Table IV. Comparison of the behaviour of clomipramine and de methyl-clomipramine after oral administration or a 2h infusion of
clomipramine 50mg (data from Evans et al. 1980)
Route Cmax (C) Cmax (DC)
[lLg/L] [lLg/L]
PO 27.6 ± 9.:} 5.0 ± 1.4
IV 77.8 ± 22.7 3.1 ± 1.1
Abbreviations: Cmax = peak plasma drug concentration; t max = time to Cmax ; AUC
C = clomipramine; DC = demethyl-clomipramine; PO = oral; IV = intravenous.
demethyl-clomipramine, respectively (Kuss &
Jungkunz 1986). The clinical relevance of this find-
ing, however, still needs to be ascertained although
it is evident that a daily dose of clomipramine
150mg is too high in a number of individuals, and
in elderly depressive patients in particular.
5. Pharmacokinetics Under
Steady-State Conditions
The common finding of all studies performed
at steady-state is the great interindividual varia-
bility in both clomipramine and demethyl-clomi-
pramine concentrations. Table V summarises some
of the findings observed during blood sampling at
steady-state. It is, however, not possible to make
strict comparisons between the different studies,
since the experimental protocols for each were quite
different. Nevertheless, some general conclusions
can be reached from this heterogeneous material.
The interpretation of steady-state data is further
complicated by the fact that high intraindividual
variability has been found in some patients, in-
cluding diurnal fluctuations that cannot be ex-
plained by the individual dosing scheme (Hullin
1980). The same observations have been made after
administration of single oral or intravenous doses
of clomipramine to healthy volunteers and de-
pressed patients (de Zeeuw et al. 1980). No satis-
factory explanations have been found for this un-
usual finding.
455
t max (C) t max (DC) AUCpo/AUClv
[hI [hI
C DC
I
5 8
0.48 1.3
(3-5) (5-12)
(0.36-0.62) (1.05-2.13)
2 2
= area under the concentration-time curve;
5.1 Effect of Age
Although there are no formal studies on the
pharmacokinetics of clomipramine in elderly
patients, there are numerous reports that steady-
state concentrations of both the drug and de me-
thy I-clomipramine are increased in this group (see
table V). The practical consequence of this observ-
ation is that daily doses of clomipramine must be
reduced in elderly patients seen as a sub-popula-
tion, but that some of these patients need a daily
dose identical to that given to younger patients.
5.2 Pharmacokinetic Drug-Drug Interactions
Pharmacokinetic interactions between imipra-
mine or desipramine and neuroleptic drugs (e.g.
phenothiazines or butyrophenones) have been re-
ported for more than 15 years (Bock et al. 1983;
Boissier et al. 1975; Gram 1975; Gram & Overo
1972; Siris et al. 1982). More recently, the same
findings have been confirmed for clomipramine
(Balant-Gorgia et al. 1986). In vivo studies with
desipramine (Hirschowitz et al. 1983; Nelson & Jat-
low 1980) and nortriptyline (Gram et al. 1974; Loga
et al. 1981) have shown similar results, indicating
that the main effect of neuroleptics on tricyclic
antidepressant metabolism is inhibition of their
hydroxylation, leading to a marked increase in their
steady-state blood concentrations. The same mech-
anism is probably also involved for the dimethy-
lated compounds. For clomipramine, the interac-
456 Clin. Pharmacokinet. 20 (6) 1991

tion leads to a marked, and clinically significant,
increase of demethyl-clomipramine concentra-
tions, whereas clomipramine is much less influ-
enced due to its de methylation pathway to the me-
tabolite (Balant-Gorgia et al. 1989b).
Other, less common interactions have been de-
scribed with allopurinol (Balant-Gorgia et al. 1987).
5.3 Environmental Factors
As seen in table V, smoking has been shown to
decrease the steady-state concentrations of clomi-
pramine, but only marginally affects those of de-
methyl-clomipramine (John et al. 1980), probably
because smoking increases demethylation clear-
ance without affecting hydroxylation (Gex-Fabry
et al. 1990). This observation is in agreement with
the known fact that cigarette smoking induces
cyto<;hrome P448 enzymes with little or no effect
on some cytochromes P450 (J usko 1979).
Alcohol also has a differential effect on the de-
methylation and hydroxylation of clomipramine.
Chronic alcoholics appear to have a decreased de-
methylation clearance, whereas hydroxylation
seems to be normal (Balant-Gorgia et al. 1989a).
It is interesting to note that this phenomenon lasts
2 or more weeks after cessation of alcohol intake
(Balant-Gorgia, unpublished observation). This is
in contrast with the effect of long term alcohol in-
take on the pharmacokinetics of imipramine since
it was found that the CL of that drug was increased
(probably due to enzyme induction) in alcoholics
compared with healthy volunteers (Ciraulo et al.
1982, 1988). Differences in smoking habits or al-
cohol intake pattern may partially explain the ob-
served differences, which warrant further investi-
gation.
6. Clomipramine Blood Concentrations
and Clinical Response
Numerous studies have been conducted with the
objective of finding a relationship between blood
concentrations of tricyclic antidepressants and
clinical outcome, but despite all efforts this subject
is highly controversial (Montgomery 1980). In the
present review only a few such studies are pre-
sented (table VI) in order to highlight the problems

Table V. Steady-state concentrations (CSS) of clomipramine (C) and demethyl-clomipramine (DC) after oral administration

No. of Dose Age CSs ("gIL) Comments Reference

subjects (mg/day) (y)
C DC

7 3 x 25 29-54 20-70 38-185 No direct relationship between C and Jones & Luscombe
dose, whereas DC was correlated (1977)
5 1x 75 36-60 17-50 30-104
8 3x 10 23-67 10-51 42 ± 9
8 1x 30 45 ± 7 26 ± 6 22 ± 5
27 3x 50 19-68 24-185 36-289 Increasing concentration with age; Traskman et al.
DCIC ratio variable between 1.1 and (1979)
5.2
28 1 x 25 18-75 10-35 15-40 Effects of smoking and age John et al. (1980)
10 200 23-50 75-296 41-540 C was also administered to steady- De Cuyper et al.
state by the intramuscular route: in (1981)
some patients DC concentrations
were low, in others not detectable
14 150 21-64 88-351 71-283 Blood samples taken about 12h after Burch et al. (1982)
the last dose are probably most
adequate for drug concentration
monitoring. DC concentration still
rising on day 15
Clinical Pharmacokinetics of Clomipramine 457

Table VI. Relationship between blood concentrations of tricyclic antidepressants and clinical efficacy

No. of Diagnosis Duration of Dose C·· ("gIL) Comments Reference

subjects treatment (mg)
C DC
(weeks)1
analytical
method

14 Endogenous 3/GLC 150 40-480 140-1050 No relation with C. but Broadhurst et

depression. inverse U-shaped al. (1977)
hospitalised relationship with DC
20 Depression 41 specific for 50 15-135 5-345 No relationship. Two of 20 Gringras et al.
C and DC patients had abnormally (1977)
high DC concentrations
70 Depression. 4/specific for 30 About 50% drop-out. no Miller et al.
general C and DC 75 relationship. Steady-state (1977)
practice concentrations reached
patients after 1 week
50 Depression, 3/GLC IV then 40-380 25-1055 No relation with C. but Della Corte et
hospitalised 150 PO inverse U-shaped al. (1979)
relationship with DC. IV
treatment resulted in high
C concentrations. and PO
in high DC concentrations
42 Endogenous 3/HPLC 150 25-185 35-275 Correlation with DC, in Traskman et al.
depression, relationship to 'serotonin (1979)
hospitalised status'. Only C
concentrations were
related to age
31 Depression. 4/GLC Variable Linear correlation with C + Vandel et al.
hospitalised DC concentrations. Alcohol (1982)
and tobacco modified the
C/DC ratio
62 Major 4/GLC 125 Relationship with C and Favarelli et al.
depression, DC. A threshold level of C + (1984)
hospitalised DC between 160 and 200
"gIL was detected
18 Major 4/HPLC, RIA 150 40-145 90-325 Relationship with DC and Piollet et al.
depression C + DC. Different (1988)
analytical methods were
compared

Abbreviations: C·· = plasma drug concentration at steady-state; GLC = gas-liquid chromatography; HPLC = high performance liquid
chromatography; RIA = radioimmunoassay; C = clomipramine; DC = demethyl-clomipramine; IV = intravenous; PO = oral.

encountered, rather than to reach a final conclu-
sion on this difficult topic.
The first difficulty is the choice of a daily dose.
If 'extremely' high and low concentrations are an
objective of the study it is probably necessary to
use more than I dose level, although the phar-
macokinetic variability of clomipramine and de-
methyl-clomipramine is such that steady-state blood
concentrations naturally have a wide range. Once
this problem has been solved, it is probably useful
to take more than I blood sample in order to as-
certain that steady-state has been reached and that
the concentrations are stable over time. As an ex-
ample, Broadhurst et al. (1977) used as an 'index
458
of change in severity of depression' the percentage
reduction in the Hamilton score between the third
and the twenty-first days of treatment. The authors
simultaneously observed that although the plasma
concentrations of clomipramine (mean half-life of
about 1 day) did not increase after the third day,
this was not the case for demethyl-clomipramine
(mean half-life of about 3 days), which doubled its
concentration between the third and twenty-first
days. This observation emphasises the difficulty of
performing this type of study with clomipramine
because of the unique pharmacokinetic properties
of the metabolite, since desipramine and nortrip-
tyline have much shorter half-lives of about 1 day.
On the other hand, Miller et al. (1977) observed
that concentrations of clomipramine and de me-
thyl-clomipramine reached steady-state after 1
week. In this context it is important to note that
the observation time for this type of depression is
usually 3 to 4 weeks, i.e. exactly the time needed
for demethyl-clomipramine to reach steady-state.
A second problem is the existence of at least 2
active principles with different pharmacological
properties. Their ratio changes with time, since they
reach steady-state after 1 and 3 weeks, respectively.
This is further complicated by the facts that the
ratio of c1omipramine/demethyl-clomipramine
steady-state concentrations shows a high degree of
interindividual variability, that it is influenced by
alcohol and tobacco intake (Vandel et al. 1982) and
that it is under strong genetic control (Balant-Gor-
gia et al. 1989b).
Piollet et al. (1988) raised a third difficulty, con-
cerning the influence of the analytical method on
the outcome of the study. It appears that studies
using radioimmunoassay have consistently failed
to demonstrate any relationship between concen-
tration and effect (Jones & Luscombe 1977; Mont-
gomery et al. 1980; Moyes et al. 1980). On the other
hand, studies using specific methods were more
successful in detecting such relationships. It is dif-
ficult to decide from the available information
whether such a finding is artifactual or reflects a
basic phenomenon.
The fourth pharmacokinetic problem is related
to the existence of hydroxylated metabolites which
Clin. Pharmacokinet. 20 (6) 1991
are pharmacologically active and probably parti-
cipate to some extent in the clinical efficacy of the
drug. They are usually not measured, and if they
were it is difficult to imagine how they should be
taken into consideration.
Besides these obstacles, it is evident that the
studies reflect the difficulties mentioned for all
clinical trials of antidepressants: number of patients,
homogeneity of diagnosis, severity of depression,
spontaneous remissions, duration of observation,
side effects, drop-outs, evaluation instruments, cri-
teria for response, and so on. D€spite these short-
comings a few important findings emerge when the
available data are analysed together.
1. There is no relationship between administered
dose and concentration of clomipramine and/or
demethyl-clomipramine. Accordingly, daily dose
is a poor predictor of treatment outcome.
2. Both clomipramine and demethyl-clomipramine
participate in the therapeutic effect. Despite their
different pharmacological profile, it is usually
satisfactory to use the sum of clomipramine and
demethyl-clomipramine as the 'drug concentra-
tion'.
3. There is good evidence that concentrations which
are 'too low' (i.e. < 150 jLg/L) are usually asso-
ciated with nonresponse. 'Too high' concentra-
tions (i.e. >450 jLg/L) are often associated with
a higher frequency of side effects, and even with
nonresponse (Balant-Gorgia et al. 1989b).
4. Although not systematically evaluated in the case
of clomipramine, the use of 'unbound concen-
tration', or the measurement of hydroxylated
metabolites, is not a necessary requirement for
the use of plasma concentrations as a guide to
treatment adequacy. Whole blood concentra-
tions are also adequate and, in addition, centri-
fugation of blood cells is not necessary (Balant-
Gorgia, unpublished observation).
5. Time to reach steady-state for demethyl-clomi-
pramine is probably not a key issue for thera-
peutic efficacy, since clomipramine seems to re-
lieve responding patients as quickly (or slowly)
as other tricyclic antidepressants. In fact about
4 to 6 weeks are necessary for complete remis-
Clinical Pharmacokinetics of Clomipramine
sion, but changes measurable on depression
scales often occur as early as I week after the
start of clomipramine pharmacotherapy when
blood concentrations of clomipramine and de-
methyl-clomipramine are above I SO ~g/L (Bal-
ant-Gorgia, unpublished observation).
7. Blood Concentration Monitoring
Analysing studies comparing blood concentra-
tions of clomipramine and demethyl-c1omipra-
mine to clinical efficacy leads to the conclusion that
the high interindividual variability is one of the
major problems related to the successful use of this
drug (as well as other tricyclic antidepressants). This
leads to the search for methods for minimising this
variability, and one of these is drug concentration
monitoring.
Monitoring of blood/plasma tricyclic concentra-
tions is still a controversial issue. Among the crit-
icisms raised are the lack of clear 'relationships'
between clinical response and steady-state concen-
trations. This is, in our opinion, an insufficient rea-
son to discard this approach since it has now been
clearly demonstrated that too low (and in some
cases too high) a blood concentration of clomipra-
mine and demethyl-c1omipramine leads to nonres-
ponse, and that concentrations that are too high
are often related to severe unwanted side effects
(section 6). Our experience in Geneva clearly shows
that the great interindividual variability of the
pharmacokinetics of this drug, associated with its
rather narrow therapeutic margin, makes clomi-
pramine an ideal candidate for blood concentra-
tion monitoring. Under these conditions, this drug
is very efficacious for the treatment of major de-
pressive episodes and safe in the vast majority of
patients.
8. Conclusions
Since the review on the pharmacokinetics of
clomipramine by Luscombe in 1979, some formal
pharmacokinetic studies have been performed in
healthy volunteers. They did not basically change
459
our understanding of the behaviour of clomipra-
mine in healthy volunteers, but allowed some
pharmacokinetic parameters to be defined with
more precision, in part because more sensitive ana-
lytical methods became available.
No formal studies appear to have been per-
formed in special subpopulations such as elderly
depressed patients, or individuals with liver or kid-
ney failure. Despite this fact, our knowledge about
the influence of genetic or environmental factors
has increased markedly. This is due mainly to 2
related factors: (a) the numerous clinical studies
conducted in depressed patients in order to see if
relationships exist between blood clomipramine and
demethyl-clomipramine concentrations and clinical
outcome; and (b) monitoring of blood concentra-
tions of tricyclic antidepressants in some clinical
centres. The use of more or less sophisticated
'population approaches' has made it possible to ex-
tract important pharmacokinetic information from
this rather 'soft' data. As a consequence, our know-
ledge of the clinical pharmacokinetic profile of
clomipramine and its main metabolites can be
considered to be satisfactory, despite the lack of
classical studies in particular subpopulations. This
nicely illustrates how a combination of formal and
observational pharmacokinetic studies using clas-
sical and population approaches could be imple-
mented in the future during phases J, II and III of
drug development.
Acknowledgements
The authors would like to thank Dr W. Riess and Dr
J.W. Faigle from Ciba-Geigy Ltd, Basel, for their valuable
help in revising the manuscript.
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de Monitoring Therapeutique, Institutions Universitaires de
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