![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
Vol. 27, Issue 9, 1078-1084, September 1999
Division of Clinical Pharmacology, Departments of Medicine and Pharmacology, Georgetown University Medical Center, Washington
 |
Abstract |
|---|
 Top
 Abstract
 Introduction
Materials and Methods
Results
Discussion
References
|
|---|
The ability of antipsychotic drugs to inhibit the catalytic activity of five cytochrome P-450 (CYP) isoforms was compared using in vitro human liver microsomal preparations to evaluate the relative potential of these drugs to inhibit drug metabolism. The apparent kinetic parameters for enzyme inhibition were determined by nonlinear regression analysis of the data. All antipsychotic drugs tested competitively inhibited dextromethorphan O-demethylation, a selective marker for CYP2D6, in a concentration-dependent manner. Thioridazine and perphenazine were the most potent, with IC50 values (2.7 and 1.5 µM) that were comparable to that of quinidine (0.52 µM). The estimated Ki values for CYP2D6-catalyzing dextrorphan formation were ranked in the following order: perphenazine (0.8 µM), thioridazine (1.4 µM), chlorpromazine (6.4 µM), haloperidol (7.2 µM), fluphenazine (9.4 µM), risperidone (21.9 µM), clozapine (39.0 µM), and cis-thiothixene (65.0 µM). No remarkable inhibition of other CYP isoforms was observed except for moderate inhibition of CYP1A2-catalyzed phenacetin O-deethylation by fluphenazine (Ki = 40.2 µM) and perphenazine (Ki = 65.1). The estimated Ki values for the inhibition of CYP2C9, 2C19, and 3A were >300 µM in almost all antipsychotics tested. These results suggest that antipsychotic drugs exhibit a striking selectivity for CYP2D6 compared with other CYP isoforms. This may reflect a remarkable commonality of structure between the therapeutic targets for these drugs, the transporters, and metabolic enzymes that distribute and eliminate them. Clinically, coadministration of these medicines with drugs that are primarily metabolized by CYP2D6 may result in significant drug interactions.
| |
Introduction |
|---|
|
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
|
|---|
It is not unusual for patients
with psychiatric disorders to take combinations of many drugs including
more than one antipsychotic, antidepressants, antimanic drugs, or
benzodiazepines (Rosholm et al., 1994
). These patients are at high risk
for drug interactions that may be masked by the positive effects or
side effects of antipsychotics themselves. Many authors have described
pharmacokinetic and pharmacodynamic interactions with antipsychotics
(Goff and Baldessarini, 1993; Meyer et al., 1996). Most of these have
focused on the effect of inhibitors and/or inducers on the
pharmacokinetics of antipsychotics, not on the effect of antipsychotics
on coadministered drugs.
The genetically polymorphic cytochrome P-450
(CYP)2 2D6
has been implicated in the metabolism of many
antipsychotic agents, including thioridazine, perphenazine,
chlorpromazine, fluphenazine, haloperidol, zuclopenthixol, risperidone,
and sertindole (Michalets, 1998). This enzyme is also important in the
metabolism of other drugs that are commonly prescribed to patients with
psychiatric disorders, e.g., tricyclic antidepressants (nortriptyline,
desipramine, amitriptyline, imipramine, and clomipramine) and selective
serotonin reuptake inhibitors, including fluoxetine and paroxetine
(Taylor and Lader, 1996; Sproule et al., 1997). CYP1A2 and CYP3A are
also involved in the metabolism of antipsychotic drugs including
clozapine, olanzapine, pimozide, and haloperidol (Eiermann et al.,
1997; Pan et al., 1997; Desta et al., 1998). Drugs that inhibit these enzymes would be expected to cause increases in the plasma
concentration of coadministered antipsychotic drugs (Goff and
Baldessarini, 1993; Ereshefsky, 1996; Michalets, 1998). These increases
may, in turn, lead to the development or aggravation of
antipsychotics-induced side effects including cardiac toxicity,
anticholinergic side effects, or orthostatic hypotension (Ereshefsky,
1996; Desta et al., 1999).
Antipsychotics themselves seem to inhibit the metabolism of some
coadministered drugs, although the number of publications on this
subject is limited. Haloperidol, thioridazine, perphenazine, and
chlorpromazine were reported to increase the plasma concentrations of
nortriptyline, desipramine, and propranolol, which are substrates of
CYP2D6 and 1A2 (Nelson and Jatlow, 1980; Goff and Baldessarini, 1993;
Maynard and Soni, 1996). In addition, it is possible that the
antipsychotic drugs that are substrates of CYP2D6 and/or CYP1A2 may
have the potential to inhibit other coadministered antipsychotics or
antidepressants that are substrates of CYP2D6 or 1A2. However, there
are few data on which CYP isoform is inhibited by antipsychotics (Ring
et al., 1996; Ereshefsky, 1996). In addition, a study that directly
compares inhibitory effects of antipsychotics on various CYP isoforms
is required to predict the relative potential of these drugs to inhibit
the metabolism of a drug that is a substrate of a specific CYP isoform.
Therefore, this study was conducted to assess the relative potential
for eight different antipsychotic drugs to inhibit isoform-specific
substrates of CYP1A2, CYP2D6, CYP2C9, CYP2C19, and CYP3A using human
liver microsomes (HL) in vitro.
| |
Materials and Methods |
|---|
|
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
|
|---|
Chemicals.
Chlorpromazine, perphenazine, fluphenazine, thioridazine,
cis-thiothixene, haloperidol, clozapine, phenacetin,
acetaminophen, dextromethorphan hydrobromide, tolbutamide, quinidine
sulfate, glucose 6-phosphate (G-6-P), glucose 6-phosphate dehydrogenase (G-6-PDH), 
-nicotinamide adenine dinucleotide phosphate, and EDTA
were purchased from Sigma Chemical Co. (St. Louis, MO). Risperidone was
obtained from Research Diagnostics, Inc. (Flanders, NJ).
4-Methylhydroxytolbutamide was purchased from Ultrafine Chemicals
(Manchester, England) and levallorphan from U.S.P.C. (Rockville,
MD). Dextrorphan tartrate and 3-methoxymorphinan were obtained
from Hoffman-La Roche Inc. (Nutley, NJ). Omeprazole and
5-hydroxyomeprazole were generous gifts from Dr. Tommy Anderson
(Clinical Pharmacology, Astra Hässle AB, Mölndal, Sweden).
N-(4-hydroxyphenyl)butanamide was kindly provided by Dr.
John Strong (Division of Clinical Pharmacology, Center for Drug
Evaluation and Research, United States Food and Drug Administration,
Rockville, MD). All other chemicals and reagents used were of the
highest commercially available quality.
HL.
Human liver tissues (n = 11), medically unsuitable for
liver transplantation, were acquired under the auspices of the
Washington Regional Transplant Consortium (Washington, DC) and frozen
at 
80°C within 3 h of the cross-clamp time. HL were prepared
as described previously (Ko et al., 1997) and protein concentrations were determined by the Bradford method of Pollard et al. (1978). The
microsomal pellets were resuspended to a protein concentration of 10 mg/ml in reaction buffer (0.1 M sodium and potassium phosphate, 1.0 mM
EDTA, 5.0 mM MgCl2, pH 7.4) and some of the
microsomal preparations were mixed together with others using equal
volumes of each preparation used (mixed human liver, MHL). Microsomal suspensions were stored at 80°C and thawed before study.
Inhibition Studies.
The effects of antipsychotic drugs on the metabolism of five different
CYP isoform-specific substrates were studied: phenacetin O-deethylation for CYP1A2 (Tassaneeyakul et al., 1993),
dextromethorphan O-demethylation for CYP2D6 (Broly et al.,
1989), tolbutamide 4-methylhydroxylation for CYP2C9 (Relling et al.,
1990), omeprazole 5-hydroxylation (Chiba et al., 1993; Balian et al.,
1995; Ko et al., 1997), and dextromethorphan N-demethylation
for CYP3A (Gorski et al., 1994).
) was measured by a minor modification of
the method described by Ko et al. (1997). The incubation mixtures (final volume, 250 µl) contained NADPH-regenerating system (1.3 mM
-nicotinamide adenine dinucleotide phosphate, 3.3 mM G-6-P, 3.3 mM
MgCl2, and 1 U/ml G-6-PDH) and phenacetin
(25-150 µM) with or without antipsychotic drug (concentration 1-100
µM) in 0.1 M phosphate buffer (pH 7.4). Reactions were started by
adding microsomes (HL-7, -14, and -G, final concentration 0.25 mg/ml), incubated at 37°C for 30 min, and terminated by placing the samples on ice and adding 1.0 ml of acetonitrile with 2 µg of internal standard, N-(4-hydroxyphenyl)butanamide. The assay of
acetaminophen and phenacetin in reaction mixtures were carried out as
described previously (Ko et al., 1997). The enzyme activity was
determined by acetaminophen formation rate from phenacetin and was
expressed as the quantity of acetaminophen formed per unit of protein
concentration and time.
The CYP2D6- and 3A-catalyzed dextromethorphan O- and
N-demethylation were evaluated by measurement of dextrorphan
and 3-methoxymorphinan formed, respectively (Broly et al., 1989; Gorski
et al., 1994; von Moltke et al., 1998). Thirty-minute
incubations of dextromethorphan (10-75 µM for
O-demethylation and 100-750 µM for
N-demethylation), NADPH-regenerating system, and HL-10, -29, and -D for CYP2D6, and HL-10 and -B for CYP3A, final concentration 0.25 mg/ml, were performed for 30 min without or with the addition of
antipsychotic drugs tested (1-100 µM) or quinidine (0.01-10 µM)
as a positive control. To evaluate the possible contribution of
metabolism to CYP2D6 inhibition, mixtures of NADPH-regenerating system
and antipsychotic drugs (25 µM) with HL were preincubated for 20 min.
After this, dextromethorphan (25 µM) was added to the reaction
mixture and incubated at 37°C for a further 30 min to measure
dextrorphan formation rate. The HPLC assay with fluorescence detector
was done as described previously (Ko et al., 1997).
The CYP2C9-catalyzed 4-methylhydroxylation of tolbutamide (Relling et
al., 1990) was measured from 1-h incubations of tolbutamide (25-200
µM) without or with an antipsychotic drug (concentration 1-100
µM), NADPH-regenerating system, and HL-29 and -B (final concentration
0.5 mg/ml) in 250 µl of final reaction mixture. The enzymatic
reaction was terminated by adding 1 ml of ice-cold methylene chloride,
15 µl of 1 N HCl and 25 µl of 0.01 mg/ml of chlorpropamide as an
internal standard. Tolbutamide, 4-hydroxytolbutamide, and
chlorpropamide were extracted with vigorous shaking on the vortex mixer
for 10 min. After discarding the supernatant from centrifugation, the
remaining organic phase was dried in the Speedvac (Savant Instruments
Inc.) and reconstituted with 100 µl of HPLC mobile phase consisting
of 35% acetonitrile in 0.022%
H3PO4 at pH 2.65 adjusted
with triethylamine. Tolbutamide and 4-hydroxytolbutamide were separated
on an Alltech Spherisorb DDS (250 × 4.6 mm, 5 µM) with Waters
Novapak C18 guard column at a flow rate of 0.8 ml/min and detected by Waters 490 UV detector set at 240 nm wavelength.
CYP2C19 activity was assayed by measuring 5-hydroxyomeprazole formation
(Chiba et al., 1993) from 1-h incubations of omeprazole (25-150 µM)
without and with an antipsychotic drug (1-100 µM), NADPH-regenerating system, and HL-29 and -B (final concentration 0.5 mg/ml). The reaction was terminated by adding 100 µl of ice-cold acetonitrile with 40 µl of 0.25 mg/ml phenacetin, the internal standard. After centrifugation at 14,000 rpm in a microfuge for 5 min,
150 µl of the supernatant was injected into the HPLC system. Omeprazole, 5-hydroxyomeprazole, and phenacetin were separated on a
Microsorb C18 column (150 × 4.6 mm) with a
flow rate of 1.2 ml/min in a mobile phase of 40% methanol with 1.4%
triethylamine (pH 7.4 adjusted with phosphoric acid). Chromatograms
were obtained from a Waters 484 UV detector with the wavelength set at
302 nm.
Data Analysis.
The apparent kinetic parameters for CYP isoform-specific metabolite
formation (Vmax,
Km) and enzyme inhibition by antipsychotic drugs (IC50, Ki) were
determined by nonlinear least square regression analysis using
WinNonlin Version 1.5 (Scientific Consulting, Inc., Apex, NC). These
data were fitted to different models of enzyme inhibition: pure and
partial competitive inhibition, noncompetitive inhibition, mixed type
inhibition, and uncompetitive inhibition (Segel, 1975). The type of
inhibition was determined by following several criteria: visual
inspection of Lineweaver-Burk double reciprocal plots, Dixon plots, and
secondary plots of Lineweaver-Burk plot versus antipsychotic
concentrations; the size of the sum of squares of the residuals, Akaike
Information Criteria and Schwartz Criteria values, the S.E. and
95% confidence interval of the parameter estimates, and the random
distribution of the residuals from the nonlinear regression analysis.
![<UP>for competitive inhibition, % inhibition</UP>=<FR><NU>[<UP>I</UP>]</NU><DE>[<UP>I</UP>]+K<SUB><UP>i</UP></SUB>(1+[<UP>S</UP>]/K<SUB><UP>m</UP></SUB>)</DE></FR>×100](/content/vol27/issue9/fulltext/1078/img001.gif)
|
</NU><DE>[<UP>I</UP>](1+[<UP>S</UP>]/&agr; · K<SUB><UP>m</UP></SUB>)+K<SUB><UP>i</UP></SUB>(1+[<UP>S</UP>]/K<SUB><UP>m</UP></SUB>)</DE></FR>×100](/content/vol27/issue9/fulltext/1078/img002.gif)
|
is the factor by which Km
changes when inhibitor occupies the enzyme and the values of and
Ki entered into these formulae were
generated from this study. For these calculations, the substrate
concentration [S] was assumed as 1/10 of
Km value because the therapeutic range of
plasma drug concentration is usually much less than its
Km value. The concentrations of
antipsychotic drugs used in these calculations were the median values
of the therapeutic range of plasma drug concentrations (Javaid, 1994; Hardman et al., 1995) and 100-fold concentrations of these
median values with the assumption of high accumulation of all
antipsychotics in liver tissue (Dinovo et al., 1978; Forsman et al.,
1981).
| |
Results |
|---|
|
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
|
|---|
The apparent metabolic constants (Km, Vmax) of HL used in these experiments were calculated from the nonlinear regression of the data on specific CYP isoform-catalyzed formation of metabolites (Table 1). Compared with Km values, Vmax values of the metabolic reactions tested showed large variations between different livers.
|
All antipsychotic drugs preferentially inhibited CYP2D6-catalyzed dextromethorphan O-demethylation compared with other CYP isoform-catalyzed reactions (Fig. 1). Among the antipsychotic drugs tested, thioridazine and perphenazine were the most potent inhibitors and decreased the dextrorphan formation rate to 26.5 and 19.7% of control activity at 10 µM, and 11.4 and 10.7% of control activity at 25 µM, respectively. The inhibitory potency of these drugs on dextromethorphan O-demethylation was comparable to the inhibitory effect of 10 to 25 µM quinidine (Fig. 2). The estimated mean IC50 values for thioridazine and perphenazine were 2.7 ± 0.5 and 1.5 ± 0.3 µM, respectively. The IC50 of quinidine, a potent CYP2D6 inhibitor, was estimated to be 0.52 ± 0.2 µM under these conditions. The estimated IC50s of chlorpromazine, fluphenazine, and haloperidol were 9.7, 16.3, and 14.4 µM, respectively (Fig. 2). Cis-thiothixene, clozapine, and risperidone exhibited weaker inhibition than the other drugs tested, with mean IC50s estimated to be 136.6, 92.2, and 39.1 µM, respectively.
|
|
The double reciprocal plots, Dixon plots, and secondary plots of slope of double reciprocal plots versus inhibitor concentration of chlorpromazine, fluphenazine, cis-thiothixene, clozapine, and risperidone showed the same type of inhibition. Representative plots for chlorpromazine are presented in Fig. 3. All these plots indicated that chlorpromazine, fluphenazine, cis-thiothixene, clozapine, and risperidone competitively inhibited dextromethorphan O-demethylation. In addition, the inhibitory effects of these antipsychotic drugs were best fitted to a pure competitive inhibition model by nonlinear regression analysis using WinNonlin.
|
The double reciprocal plot, Dixon plot, and secondary plot versus antipsychotic concentration showed hyperbolic curves when thioridazine, perphenazine, and haloperidol were incubated as inhibitors of dextromethorphan O-demethylation. The plots for perphenazine are shown in Fig. 4. Partial competitive inhibition was the best model to describe these data.
|
The Ki values of antipsychotic drugs were obtained from nonlinear regression using the appropriate pure or partial competitive inhibition models (Table 2). Perphenazine and thioridazine showed the lowest Ki values at around 1 µM. Mean Ki values of chlorpromazine, haloperidol, and fluphenazine were 6.3, 7.2, and 9.4 µM, respectively. The drug with the highest Ki was cis-thiothixene (65 µM). Of note, the atypical antipsychotics clozapine and risperidone, with estimated Ki values of 39 and 21.9 µM, were weaker inhibitors than the conventional antipsychotic drugs tested.
|
A 20-min preincubation increased the inhibition by cis-thiothixene, haloperidol, and clozapine on CYP2D6-catalyzed dextromethorphan O-demethylation by 20% over control without preincubation (Fig. 5). No significant increase of inhibition was observed from the preincubation of thioridazine, perphenazine, fluphenazine, chlorpromazine, or risperidone.
|
The antipsychotic drugs had no remarkable inhibitory effect on CYP1A2-, CYP2C9-, CYP2C19-, or CYP3A-catalyzed reactions with the exception of moderate inhibition by fluphenazine and perphenazine of CYP1A2-catalyzed phenacetin O-deethylation (Fig. 1B). A competitive inhibition model was best-fitted to the data for inhibition by fluphenazine and perphenazine of CYP1A2-catalyzed phenacetin O-deethylation. The estimated mean Ki values were 40.2 µM for fluphenazine and 65.1 µM for perphenazine.
Thioridazine, fluphenazine, and clozapine showed very weak inhibition of CYP2C9-catalyzed tolbutamide 4-methylhydroxylation, with estimated mean Ki values of 174.6, 350, and 327.3 µM, respectively (Fig. 1C). The CYP2C19-catalyzed formation of 5-hydroxyomeprazole and CYP3A-catalyzed formation of 3-methoxymorphinan from dextromethorphan were not inhibited by any of the antipsychotics tested (Fig. 1, D and E). The Ki values were estimated to be >300 µM from the best-fitted competitive or noncompetitive inhibition models.
| |
Discussion |
|---|
|
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
|
|---|
In this study, all of the antipsychotic drugs tested strongly and
competitively inhibited the CYP2D6-catalyzed O-demethylation of dextromethorphan, but they had no notable effect on the other CYP
isoforms evaluated. It was interesting that clozapine, which is
metabolized mainly by CYP1A2 and CYP3A4 (Eiermann et al., 1997), also
showed competitive inhibition of CYP2D6-catalyzed dextromethorphan O-demethylation with a Ki of
39.0 µM, but no remarkable inhibition of CYP1A2- and CYP3A-catalyzed
enzyme reactions. There is a precedent for inhibition of CYP2D6 by
drugs whose metabolism is not catalyzed by it. Quinidine and
halofantrine compete for the substrate-binding site of CYP2D6 but are
not metabolized by it (Otton et al., 1988; Halliday et al., 1995).
Pimozide, an antipsychotic drug, is another example. Pimozide is
metabolized by CYP3A and CYP1A2 and not by CYP2D6, but it does inhibit
CYP2D6 (Desta et al., 1998). From the data obtained from this study, it
seems clear that almost all antipsychotic drugs have the potential to
inhibit CYP2D6. Many of these drugs (chlorpromazine, fluphenazine,
perphenazine, haloperidol, thioridazine, risperidone,
trifluperidol, and zuclopenthixol) are also metabolized by this
CYP isoform (Taylor and Lader, 1996; Michalets, 1998). It follows that
antipsychotic drugs may develop pharmacokinetic drug interactions with
coadministered antipsychotics and antidepressants (amitriptyline,
imipramine, nortriptyline, desipramine, clomipramine, maprotiline,
trazodone, paroxetine, and fluoxetine) that are not only metabolized by
CYP2D6 but also inhibit it (Taylor and Lader, 1996; Meyer et al., 1996;
Sproule et al., 1997). These interactions may cause serious adverse
effects due to the increase in plasma concentrations of drugs that have low therapeutic indices (Goff and Baldessarini, 1993; Michalets, 1998)
if these data are confirmed in clinical studies.
Available data on the inhibition of drug metabolism in vitro by
antipsychotics are confined to studies of a small number of drugs,
including thioridazine, chlorpromazine, olanzapine, and clozapine (Von
Bahr et al., 1985; Murray and Reidy, 1989; Ring et al., 1996;
Ereshefsky, 1996). Our data provide a comprehensive assessment of the
ability of these drugs to interact with CYP isoforms important to drug
metabolism in a single study, using consistent conditions. Von Bahr et
al. (1985) reported the estimated Ki values
of thioridazine and chlorpromazine for CYP2D6-catalyzed desmethylimipramine 2-hydroxylation to be 0.75 and 6 µM,
respectively. Clozapine was reported to inhibit CYP2D6-catalyzed
bufuralol 1'-hydroxylation with a Ki of 19 µM and CYP2C19-catalyzed 4-hydroxy S-mephenytoin formation
with a Ki of 69 µM (Ring et al., 1996).
In our study, clozapine competitively inhibited CYP2D6-catalyzed
dextromethorphan O-demethylation with a
Ki of 39 µM and noncompetitively
inhibited CYP2C19-catalyzed omeprazole 5-hydroxylation with a
Ki of 316 µM, respectively. The relative
inhibitory potency of antipsychotics reported by Ring et al. (1996)
seems similar to ours even though the estimated
Ki values of the antipsychotics are
different. Differences in the Ki values may
be caused partly by differences in the substrates used (Boobis, 1995).
To estimate the clinical relevance of CYP2D6 inhibition by
antipsychotics, we compared the expected relative inhibitory potency in
vivo to the known therapeutic plasma concentrations of antipsychotic drugs (Javaid, 1994; Hardman et al., 1995). For this purpose, we
calculated the potency of inhibition relative to the therapeutic concentration ([I]/Ki), a measure of
specificity as well as potency of an inhibitor (Boobis, 1995) and the
predicted percent inhibition as described (Table
3). Thioridazine showed the highest
[I]/Ki, with a value of 1.46. Those
of chlorpromazine and clozapine were 0.06 and 0.04, respectively. The
[I]/Ki of the remaining drugs were as
follows: perphenazine (0.0069) > haloperidol (0.0039) > risperidone (0.0007) > fluphenazine = cis-thiothixene (0.0003). The predicted percent inhibition
by each antipsychotic drug tested, calculated using these
Ki values, is presented in Table 3.
|
According to this prediction, thioridazine would be the only
antipsychotic drug tested that would significantly inhibit CYP2D6 in
vivo. However, chlorpromazine, clozapine, perphenazine, haloperidol, and even fluphenazine have been reported to increase the plasma concentrations of nortriptyline, desipramine, imipramine, and propranolol, which are at least partly metabolized by CYP2D6 (Goff and
Baldessarini, 1993; Riskin, 1994; Maynard and Soni, 1996; Mulsant et
al., 1997). This under-prediction might be the result of accumulation
of drugs in the liver, or the contribution of metabolites to CYP2D6
inhibition. The concentration of haloperidol in liver tissue has been
reported to be 900-fold higher than that in plasma of 19 cholecystectomized patients 14 h after a single oral dose of 5 to
10 mg haloperidol (Forsman et al., 1981). Similarly, the concentration
of thioridazine and its metabolites in liver tissue was 3- to 20-fold
higher than that in blood obtained postmortem (Dinovo et al., 1978).
There is evidence that metabolism may contribute to the inhibition of
CYP2D6-catalyzed dextromethorphan O-demethylation. After a
20-min preincubation, the inhibitory effects of haloperidol, cis-thiothixene, and clozapine were increased (Fig. 5). Many
antipsychotic drugs seem to have a clinical potential to inhibit
CYP2D6-catalyzed enzyme reactions due to their low
Ki values, the contribution of metabolites
to this inhibition, and the extensive accumulation of parent and
metabolites in liver tissue despite high plasma protein binding (Dinovo
et al., 1978; Forsman et al., 1981; Javaid, 1994).
Our data that demonstrate that thioridazine has the most potent
inhibitory effect on CYP2D6 in vitro are consistent with the in vivo
study of Spina et al. (1991). They reported that the prevalence of
subjects whose metabolic activity was consistent with the poor metabolizer phenotype of debrisoquine was higher in patients under thioridazine monotherapy (63.2%) than in patients taking
chlorpromazine (44.4%) or haloperidol monotherapy (27.8%).
Most antipsychotic drugs seem to be highly selective inhibitors of
CYP2D6. We studied the effect of antipsychotic drugs on CYP isoforms
across a wide range of concentrations including 4 different substrate
concentrations and 7 different antipsychotic concentrations to compare
quantitatively the inhibitory potential of antipsychotic drugs tested.
Most drugs showed over a 100-fold difference between the estimated
Ki values for CYP2D6 and the Ki values for other CYP isoforms.
Fluphenazine is the only exception in that it showed a 4-fold
difference between Ki values for CYP2D6 and
CYP1A2. This has a number of important implications. Firstly, all
antipsychotic drugs may have a common structure that allows interaction
with CYP2D6. Strobl et al. (1993) described a pharmacophore model for
CYP2D6 in which at least one aromatic ring and a tertiary nitrogen atom
that is protonated under physiologic condition are required. Most
antipsychotic drugs tested do have an aromatic ring and tertiary
nitrogen. Secondly, it is possible that antipsychotics inhibit CYP2D6
activity in the brain and that this may contribute to their therapeutic
effects. CYP2D6 has been reported to be expressed in human brain and
its pharmacological and immunological characteristics are similar to
those of CYP2D6 from bovine and human liver tissues (Niznik et al.,
1990; Gilham et al., 1997). Thirdly, the considerable evidence of
structural and functional homogeneity between CYP2D6 and the dopamine
transporter supports the concept that there may be a similarity between
the therapeutic target of these drugs and substrates for CYP2D6
(Tyndale et al., 1991; Hiroi et al., 1997). This link appears analogous
to the noted similarities between substrates of CYP3A4 and of
P-glycoprotein (Zhang et al., 1998; Fischer et al., 1998).
In conclusion, we have conducted a comprehensive evaluation of the effects of eight antipsychotic drugs on five CYP isoforms across a wide range of substrate and antipsychotic concentrations using in vitro human liver microsomal preparations. All the antipsychotics we tested inhibited CYP2D6, but showed no notable inhibition of CYP1A2, CYP2C9, CYP2C19, or CYP3A. These findings suggest that all antipsychotic drugs have the potential to cause pharmacokinetic drug interactions with drugs that are metabolized by CYP2D6, but it is equally important to note that they are unlikely to cause significant pharmacokinetic interactions with drugs that are primarily metabolized by other CYP isoforms. Some antipsychotics are sufficiently selective that they may be able to serve as selective CYP2D6 inhibitors. Lastly, our data suggest that all antipsychotics have a common structure that allows binding to CYP2D6.
| |
Footnotes |
|---|
Received January 21, 1999; accepted May 7, 1999.
1 Presented in part at the 99th meeting of the American Society for Clinical Pharmacology and Therapeutics in New Orleans, LA, March 1998.
This study was supported in part by a Shannon Director's award (D.A.F.) R55-GM56898, and by National Institute of General Medical Sciences (Bethesda, MD) Grants R01-GM56898-01 and T32-9M08386. J.-G.S. was supported by a Merck Sharp & Dohme International Fellowship Award in Clinical Pharmacology.
Send reprint requests to: Dr. David A. Flockhart, M.D., Ph.D., Assistant Professor of Medicine and Pharmacology, Division of Clinical Pharmacology, Georgetown University Medical Center, 3900 Reservoir Road NW, Washington, DC 20007. E-mail: FLOCKHAD{at}medlib.georgetown.edu
| |
Abbreviations |
|---|
Abbreviations used are: CYP, cytochrome P-450; G-6-P, glucose 6-phosphate; G-6-PDH, glucose 6-phosphate dehydrogenase; HL, human liver microsomes; MHL, mixed human liver microsomes.
| |
References |
|---|
|
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
|
|---|
)-cocaine and nucleotide sequence identity to human hepatic P450 gene CYP2D6.
J Pharmacol Exp Ther
40:
63-68.This article has been cited by other articles:
|
|
 |
|
  A. I. Nichols, P. Fatato, M. Shenouda, J. Paul, J. A. Isler, R. D. Pedersen, Q. Jiang, S. Ahmed, and A. Patroneva The Effects of Desvenlafaxine and Paroxetine on the Pharmacokinetics of the Cytochrome P450 2D6 Substrate Desipramine in Healthy Adults J. Clin. Pharmacol., February 1, 2009; 49(2): 219 - 228. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. K. Bae, S. Cao, K.-A. Seo, H. Kim, M.-J. Kim, J.-H. Shon, K.-H. Liu, H.-H. Zhou, and J.-G. Shin Cytochrome P450 2B6 Catalyzes the Formation of Pharmacologically Active Sibutramine (N-{1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyl}-N,N-dimethylamine) Metabolites in Human Liver Microsomes Drug Metab. Dispos., August 1, 2008; 36(8): 1679 - 1688. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Kim, K.-B. Kim, H.-Y. Ku, S.-J. Park, H. Choi, J.-K. Moon, B.-S. Park, J.-H. Kim, S. S. Yea, C.-H. Lee, et al. Identification and Characterization of Potent CYP2B6 Inhibitors in Woohwangcheongsimwon Suspension, an Herbal Preparation Used in the Treatment and Prevention of Apoplexy in Korea and China Drug Metab. Dispos., June 1, 2008; 36(6): 1010 - 1015. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Dolder, M. Nelson, and Z. Deyo Paliperidone for schizophrenia Am. J. Health Syst. Pharm., March 1, 2008; 65(5): 403 - 413. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y.-J. Yoon, K.-B. Kim, H. Kim, K.-A. Seo, H.-S. Kim, I.-J. Cha, E.-Y. Kim, K.-H. Liu, and J.-G. Shin Characterization of Benidipine and Its Enantiomers' Metabolism by Human Liver Cytochrome P450 Enzymes Drug Metab. Dispos., September 1, 2007; 35(9): 1518 - 1524. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Shen, M. M. He, H. Liu, S. A. Wrighton, L. Wang, B. Guo, and C. Li Comparative Metabolic Capabilities and Inhibitory Profiles of CYP2D6.1, CYP2D6.10, and CYP2D6.17 Drug Metab. Dispos., August 1, 2007; 35(8): 1292 - 1300. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. B. Sandson, K. L. Cozza, S. C. Armstrong, G. Eckermann, B. A. Fischer, and B. Phillips Clozapine Case Series Psychosomatics, April 1, 2007; 48(2): 170 - 175. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K.-H. Liu, M.-G. Kim, D.-J. Lee, Y.-J. Yoon, M.-J. Kim, J.-H. Shon, C. S. Choi, Y. K. Choi, Z. Desta, and J.-G. Shin Characterization of Ebastine, Hydroxyebastine, and Carebastine Metabolism by Human Liver Microsomes and Expressed Cytochrome P450 Enzymes: Major Roles for CYP2J2 and CYP3A Drug Metab. Dispos., November 1, 2006; 34(11): 1793 - 1797. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H.-K. Lee, J.-K. Moon, C.-H. Chang, H. Choi, H.-W. Park, B.-S. Park, H.-S. Lee, E.-C. Hwang, Y.-D. Lee, K.-H. Liu, et al. STEREOSELECTIVE METABOLISM OF ENDOSULFAN BY HUMAN LIVER MICROSOMES AND HUMAN CYTOCHROME P450 ISOFORMS Drug Metab. Dispos., July 1, 2006; 34(7): 1090 - 1095. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. B. Sandson, S. C. Armstrong, and K. L. Cozza An Overview of Psychotropic Drug-Drug Interactions Psychosomatics, October 1, 2005; 46(5): 464 - 494. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K.-H. Liu, M.-J. Kim, W. M. Jung, W. Kang, I.-J. Cha, and J.-G. Shin LANSOPRAZOLE ENANTIOMER ACTIVATES HUMAN LIVER MICROSOMAL CYP2C9 CATALYTIC ACTIVITY IN A STEREOSPECIFIC AND SUBSTRATE-SPECIFIC MANNER Drug Metab. Dispos., February 1, 2005; 33(2): 209 - 213. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K.-A. Kim, M.-J. Kim, J.-Y. Park, J.-H. Shon, Y.-R. Yoon, S.-S. Lee, K.-H. Liu, J.-H. Chun, M.-H. Hyun, and J.-G. Shin STEREOSELECTIVE METABOLISM OF LANSOPRAZOLE BY HUMAN LIVER CYTOCHROME P450 ENZYMES Drug Metab. Dispos., October 1, 2003; 31(10): 1227 - 1234. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K.-A. Kim and J.-Y. Park INHIBITORY EFFECT OF GLYBURIDE ON HUMAN CYTOCHROME P450 ISOFORMS IN HUMAN LIVER MICROSOMES Drug Metab. Dispos., September 1, 2003; 31(9): 1090 - 1092. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J.-S. Wang, X. Wen, J. T. Backman, and P. J. Neuvonen Effect of Albumin and Cytosol on Enzyme Kinetics of Tolbutamide Hydroxylation and on Inhibition of CYP2C9 by Gemfibrozil in Human Liver Microsomes J. Pharmacol. Exp. Ther., July 1, 2002; 302(1): 43 - 49. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. Desta, G. M. Wu, A. M. Morocho, and D. A. Flockhart The Gastroprokinetic and Antiemetic Drug Metoclopramide Is a Substrate and Inhibitor of Cytochrome P450 2D6 Drug Metab. Dispos., March 1, 2002; 30(3): 336 - 343. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z. Desta, N. V. Soukhova, and D. A. Flockhart Inhibition of Cytochrome P450 (CYP450) Isoforms by Isoniazid: Potent Inhibition of CYP2C19 and CYP3A Antimicrob. Agents Chemother., February 1, 2001; 45(2): 382 - 392. [Abstract] [Full Text]
|
|
|
|
|
|
R. L. Voorman, N. A. Payne, L. C. Wienkers, M. J. Hauer, and P. E. Sanders Interaction of Delavirdine with Human Liver Microsomal Cytochrome P450: Inhibition of CYP2C9, CYP2C19, and CYP2D6 Drug Metab. Dispos., January 1, 2001; 29(1): 41 - 47. [Abstract] [Full Text]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
 |
 |
|
 |
 |
 |
), thioridazine (
), fluphenazine
(
), perphenazine (
), cis-thiothixene (
),
haloperidol (
), clozapine (X), and risperidone (
). Each data
point represents the average value for percent control activity,
obtained from two or three different liver microsomal preparations.
), 50 (*), 75 (
