Pharmacopsychiatry

Main Editor: B. Saletu (Vienna)

Original Paper
Neuropsychobiology 2001;44:126128
Analysis of the Metabolism of Haloperidol and
Its Neurotoxic Pyridinium Metabolite in
Patients with Drug-Induced Parkinsonism
K. Iwahashi
a, b
K. Anemo
c
K. Nakamura
d
I. Fukunishi
e
K. Igarashi
f
a
Health Administration Center and
b
Department of Physiology, Azabu University, Sagamihara, Departments of
c
Forensic Medicine and
d
Neuropsychiatry, Kagawa Medical College, Kagawa,
e
Tokyo Institute of Psychiatry, Tokyo,
and
f
Faculty of Pharmaceutical Science, Kobegakuin University, Kobe, Japan
K. Iwahashi, MD, PhD
Health Administration Center, Department of Physiology, Azabu University
Sagamihara City, Kanagawa 229-8501 (Japan)
Tel./Fax +81 427 69 1930, E-Mail iwahashi@azabu-u.ac.jp
ABC
Fax +41 61 306 12 34
E-Mail karger@karger. ch
www.karger.com
2001 S. Karger AG, Basel
0302282X/01/04430126$17.50/0
Accessible online at:
www.karger.com/journals/nps
Key Words
HPP W Haloperidol W Vitamin E
Abstract
The blood levels of the neurotrophic drug haloperidol
(HP) and its pyridinium metabolite, HPP
+
, have been ana-
lyzed by liquid chromatography/electrospray ionization-
mass spectrometry in 10 schizophrenic patients treated
with HP, without carbamazepine (HP, oral daily dose of
0.30.5 mg/kg body weight for more than 1 year, fe-
males, aged 41 B 8.5 years). There was a significant dif-
ference (t-test, d.f. = 8, p (t
0
= 7.2) !0.005) in the blood
HPP
+
level between the 5 patients with (18.5 B 6.4 ng/ml)
and the 5 without (6.3 B 2.4 ng/ml) severe side effects
such as drug-induced parkinsonism (Extrapyramidal
Symptom Rating Scale (ESRS) parkinsonism severity
scores 2.8 B 1.5 and 1.8 B 1.1, respectively). Moreover,
it is suggested that vitamin E may be effective for drug-
induced parkinsonism through a change in the blood
HPP
+
level. It is necessary to investigate the HPP
+
metab-
olism in psychiatric patients to avoid severe side effects
such as drug-induced parkinsonism and cardiac func-
tional disorders.
Copyright 2001 S. Karger AG, Basel
Introduction
Haloperidol, 4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-
4-oxobutyl]-4-piperidinol (HP), is an antipsychotic agent
used in the treatment of psychiatric disorders such as
schizophrenia [1]. It is known that HP can cause severe
extrapyramidal side effects including drug-induced par-
kinsonism and tardive dyskinesia, especially in patients
on long-term therapy with HP [2].
It is known that HP undergoes piperidinol O-glucoron-
ide conjugation, butyrophenone carbonyl group reduction
and oxidative N-dealkylation, and that it is oxidatively
converted to a pyridinium metabolite, 4-(4-chlorophe-
nyl)-1-[4-(4-fluorophenyl)-4-oxobutyl] pyridinium species
(HPP
+
) [36]. It has also been reported that cotreatment
with HP and a psychotropic drug, carbamazepine (CBZ),
might increase cardiac changes [e.g. lengthening of the Q
T interval (QT
c
), conduction delay and arrhythmia], like
tricyclic antidepressants with CBZ [7]. It has been re-
ported that HP may be metabolized to an active (cyto-
toxic) metabolite, the pyridinium metabolite HPP
+
, by
both CYP2D6 and CYP3A4 [8]. It was suggested that
HPP
+
derived from HP might be cytotoxic and thus cause
drug-induced parkinsonism and cardiac changes [3]. It
has been reported that CBZ might increase (induce) the
metabolism of HP and tricyclic antidepressants such as
imipramine and that in patients treated with CBZ, the
serum concentrations of these drugs themselves (HP, tri-
Without CBZ
Before treatment n = 5
Analysis of the Metabolism of Haloperidol
in Drug-Induced Parkinsonism
Neuropsychobiology 2001;44:126128 127
Table 1. Blood HPP
+
levels and CYP2D6 genotypes in schizophrenic patients with and without parkinsonism
n ESRS parkinsonism
severity score
Blood HPP
+
level, ng/ml
CYP2D6 genotype and phenotype
5 2.8B1.5
(with parkinsonism)
18.5B6.1
1
1*/1* n = 3 (wild type; normal CYP2D6 activity)
10*/10* n = 2 (intermediate metabolizer; slightly low activity)
*5/*5 n = 0 (poor metabolizer; low activity)
5 1.8B1.1
(without parkinsonism)
6.3B2.4
1
1*/1* n = 3
10*/10* n = 2
5*/5* n = 0
With CBZ 2 2.9
2.4 (with parkinsonism and
QT
c
prolongation)
15.6
21.4
1*/1* n = 1
10*/10* n = 1
1
t-test, d.f. = 8; p (t
0
= 7.2) ! 0.005.
Table 2. Effects of vitamin E on the blood HPP
+
levels in schizo-
phrenic patients with parkinsonism
ESRS parkinsonism
severity score
Blood HPP
+
level
ng/ml
2.8B1.5 18.5B6.1
1
After treatment n = 5 2.1B1.6 7.7B3.5
1
t-test, d.f. = 8; p (t
0
= 7.2) ! 0.01.
cyclic antidepressants) remained below the suggested
therapeutic ranges in patients without CBZ [911]. Also,
it may be possible that if CYP3A4 is induced by CBZ, HP
is metabolized to HPP
+
on cotreatment with CBZ much
more than on treatment without CBZ [3, 711]. However,
it is unknown if the CYP2D6 polymorphism is related
with the metabolism of HP into the pyridinium metabo-
lite. In any case, for safe treatment of psychiatric disor-
ders, it is important to clarify whether or not the pyridin-
ium metabolites of neuroleptics are cytotoxic.
In this study, we investigated the relationship between
the degree of HP side effects and the blood HPP
+
level to
clarify the side effect mechanisms of neuroleptic drugs
such as HP in psychiatric disorders.
Methods
The blood level of the HP pyridinium metabolite HPP
+
was ana-
lyzed by liquid chromatography/electrospray ionization-mass spec-
trometry in schizophrenic patients treated with HP, with/without
CBZ (HP, oral daily dose of 0.30.5 mg/kg body weight for more than
1 year, females, aged 41 B 8.5 years, CBZ 400 mg/day), after
informed consent had been obtained [3]. HPP
+
was analyzed twice,
i.e. before and after vitamin E treatment for 6 weeks in 5 patients
without CBZ. The hydrochloride salt of HPP
+
was synthesized in our
laboratory [4]. The blood level of HP has been analyzed by an
enzyme immunoassay technique [4].
The CYP2D6 genotypes of the patients were analyzed by PCR
after informed consent had been obtained [12, 13].
Results
As shown in table 1, there was a significant difference
[t test, d.f. = 8, p (t
0
= 7.2) !0.005] in the HPP
+
blood level
between 5 patients with (18.5 B 6.4 ng/ml) and 5 without
(6.3 B 2.4 ng/ml) a severe side effect, drug-induced par-
kinsonism [Extrapyramidal Symptom Rating Scale
(ESRS) parkinsonism severity scores, 2.8 B 1.5 and 1.8 B
1.1, respectively]. However, we could not relate the high
blood HPP
+
levels with the CYP2D6 genotypes [alleles,
*1/*2/*5/*10; phenotypes, wild (extensive-metabolizer)
type, intermediate type and poor-metabolizer type].
There was no CYP2D6 *5 allele and no poor-metabolizer
phenotype in either group. The frequencies of the wild
and intermediate phenotypes were the same in both
groups (wild type, 3; intermediate type, 2).
Two CBZ-treated patients (*1/*1, *10/*10) showed
high ESRS parkinsonism severity scores (2.9, 2.4) and
HPP
+
values (15.6, 21.4 ng/ml) in spite of low doses of HP
(only 0.3 mg/kg body weight/day).
As shown in table 2, research suggested that vitamin E
was beneficial in the management of drug-induced par-
kinsonism in 5 schizophrenic patients without CBZ.
128 Neuropsychobiology 2001;44:126128 Iwahashi/Anemo/Nakamura/Fukunishi/
Igarashi
Discussion
Based on the present results, it is possible to speculate
that a high blood HPP
+
level may herald side effects such
as drug-induced parkinsonism in schizophrenic patients
treated with HP, and the potential active (abnormal)
metabolism of HP to HPP
+
may not be related to the
CYP2D6 polymorphism (normal *1, mutant *5, *10
alleles). Also, it is possible that vitamin E may be effective
for drug-induced parkinsonism through a change in the
blood HPP
+
level.
HP is partially metabolized by CYP3A4 and CYP2D6.
CBZ is also metabolized by CYP3A4, and it is known that
CBZ itself induces CYP3A4. If the production of HPP
+
from HP is due to CYP3A4, it is possible to speculate
that, when HP and CBZ are used together, CYP3A4 may
be induced by CBZ and, therefore, a metabolite, HPP
+
,
derived from HP may be increased by CYP3A4 through a
drug-drug interaction. In fact, as shown in table 1, 2
patients treated with HP (only 0.3 mg/kg body weight/
day) and CBZ showed the high blood HPP
+
level and also
the QT
c
prolongation.
Recently, it has been shown that CYP3A4 is the most
important CYP isozyme involved in the biotransforma-
tion of HP and RHP (reduced haloperidol) and that the
metabolism by CYP2D6 is only a minor pathway [14]. It
has been reported that HPP
+
and a newly identified
reduced pyridinium metabolite, RHPP
+
(reduced HPP
+
),
were present in the blood and urine of HP-treated schizo-
phrenics and that the concentrations of RHPP
+
exceeded
those of HPP
+
[15]. Furukori et al. [16] reported that the
metabolism of bromperidol and reduced bromperidol
with the same chemical structure as HP and RHP might
be related with CYP3A4. From the above-mentioned
facts, it is speculated that RHP, bromperidol and reduced
bromperidol may also be metabolized by mainly CYP3A4
to a pyridinium derivative like HPP
+
[1416].
Boomershine et al. [17] reported that vitamin E is ben-
eficial in the management of a subgroup of patients with
tardive dyskinesia, while Gardos [18] suggested that atyp-
ical antipsychotics and tocopherol (vitamin E) are effec-
tive and generally well tolerated treatment options for tar-
dive dyskinesia. It is unknown whether the neuropatho-
geneses of drug-induced parkinsonism and tardive dyski-
nesia are the same or not; however, it is possible that vita-
min E may be related with the effect of scavenging of neu-
ropathogenic metabolites such as HPP
+
.
In any case, it is necessary to avoid severe side effects
such as drug-induced parkinsonism and cardiac function-
al disorders to investigate the relationship between HPP
+
metabolism and CYP3A4 on HP cotreatment of psychiat-
ric disorders. It is necessary to exclude a possible effect of
the small sample size on the conclusion in this study. Fur-
ther study with a larger population of subjects is needed.
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