Pharmacodynamic Effects of Aripiprazole and Ziprasidone with Respect to P-Glycoprotein Substrate Properties

• Abstract
• Introduction
• Materials and Methods
• Drugs
• Animals
• Brain-serum ratios
• RotaRod test
• Drug application
• Application of haloperidol and serotonin receptor ligands
• Statistics
• Results
• Discussion
• References

Abstract

Introduction:

Aripiprazole, an atypical antipsychotic drug with mixed antagonism and agonism on dopamine D₂ and serotonin receptors, is a substrate of the efflux transporter P-glycoprotein (P-gp). Here we tested the pharmacodynamic consequences of these properties in a P-gp deficient mouse model by studying the effects of aripiprazole and of ziprasidone on motor coordination.

Methods:

The motor behaviour of wild-type (WT) and P-gp deficient [abcb1ab(−/−)] mice was investigated on a RotaRod. Mice received acute injections of either aripirazole or ziprasidone. For comparison, the dopamine receptor antagonist haloperidol and serotonin receptor ligands buspirone and ketanserin were also applied.

Results:

Pharmacokinetic analyses revealed P-gp activity for aripiprazole and ziprasidone. This was indicated by 3.1- and 1.9-fold higher ratios of brain to plasma concentrations of drugs in knock-out to WT animals. Acute doses of ariprazole or ziprasidone impaired motor behaviour on the RotaRod. Effects were similar after injection of haloperidol, whereas the serotonin receptor ligands buspirone and ketanserin enhanced RotaRod performance. Genotype dependent differences of motor performance were found for aripiprazole but not for ziprasidone.

Discussion:

Evidence was given that P-gp substrate properties have pharmacodynamic consequences for aripiprazole but not for ziprasidone and thus affect dopamine receptor related motor behaviour.

Introduction

The efflux transporter P-glycoprotein (P-gp), localized in blood-tissue barriers including the blood-brain barrier (BBB) [1], plays an important role in the disposition and elimination of endogenous and exogenous substances. P-gp, originally discovered in therapy resistant tumour cells eliminating anticancer drugs, is known to transport a wide spectrum of drugs including central nervous system (CNS) acting drugs, like antidepressants (citalopram, amitriptyline) or antipsychotics (risperidone, olanzapine, aripiprazole) [2] [3] [4] [5] [6]. These drugs are obliged to reach the brain in order to display their effects. Enhanced elimination via efflux transporters has been shown to diminish the pharmacological potency of the drug. In abcb1a/1b knock-out mice, lacking P-gp, concentration differences in the brain were demonstrated for several CNS acting drugs [2] [3] [4] [5] [6]. The antipsychotic drug aripiprazole has also been identified as a substrate of P-gp [4] [7]. Aripiprazole acts as a high affinity partial agonist at dopamine D₂ and serotonin 5-HT_1A receptors and as an antagonist at 5-HT_2A and 5-HT_2C receptors [8] [9] [10]. This receptor profile is suggested to be beneficial to treat positive and negative symptoms of schizophrenia with a low risk of side effects [11]. However, in the case of P-gp substrates, reduced P-gp activity can lead to higher brain concentrations with a higher risk of side effects. Kirschbaum et al. [6] demonstrated in P-gp knock-out mice that P-gp alters not only the pharmacokinetics but also the pharmacodynamic properties of the antipsychotic risperidone. In rats, it has been shown that aripiprazole dose dependently affects RotaRod performance and produces catalepsy [12]. Evidence for a clinical relevance of P-gp substrate properties has been given for schizophrenic patients treated with atypical antipsychotic drugs. A correlation between MDR1 gene polymorphisms and changing brief psychiatric rating scale (BPRS) or positive and negative symptom scale (PANSS) scores was observed under antipsychotic therapy [13] [14] [15].

The aim of this study was to investigate pharmacodynamic consequences of aripiprazole and ziprasidone with respect to P-gp expression. Aripiprazole effects were evaluated by analysis of motor behaviour of mice typically induced by D₂-receptor antagonism [8] [16] [17] in 2 genotypes, P-gp double knock-out and wild-type (WT) mice, on the RotaRod after acute treatment. The effects of different doses of aripiprazole (partial D₂ agonist, 5-HT_2A and 5-HT_2C receptor antagonist and partial 5-HT_1A receptor agonist) were compared with those of another atypical antipsychotic ziprasidone (D₂, 5-HT_2A and 5-HT_2C receptor antagonist, partial 5-HT_1A receptor agonist) because of the similarities in the receptor profiles. Because of the heterogeneous receptor profiles of the 2 atypical antipsychotic drugs, RotaRod performance was further analyzed after acute doses of haloperidol (preferential antagonism of D₂-receptors) and the serotonin receptor ligands ketanserin (selective 5-HT₂ antagonist) and buspirone (partial 5-HT_1A receptor agonist).

Materials and Methods

Drugs

Pure drug substance of aripiprazole (98% purity) was obtained from Bristol-Myers Squibb Company (Munich, Germany). For the preparation of the solutions for i.p. injection aripiprazole was dissolved in physiological saline (B. Braun, Melsungen, Germany) to a concentration of 0.6 mg/mL. 0.1% Tween 80 (Fluka Chemie GmbH, Buchs, Switzerland) and acetic acid (98%) (Merck, Darmstadt, Germany) were added for complete dissolution. The stock solution was used for preparation of dilutions containing 1, 5, or 10 mg/kg aripiprazole with physiological saline to a total volume of 1 mL for intra peritoneal (i.p.) injection in mice. Ziprasidone for injection (Zeldox^®; Pfizer, Berlin, Germany) was used in a concentration of 20 mg/mL, the volume was adjusted to a total of 0.5 mL with physiological saline. Buspirone-HCl and ketanserin (Sigma-Aldrich, Steinheim, Germany) solutions for injection were prepared by using the same solvent as for aripiprazole. As a positive control, haloperidol (Haldol Janssen^®; Janssen-Cilag GmbH, Neuss, Germany) was implemented and also dissolved in this solvent. Stock solutions for calibration of HPLC measurements were prepared by mixing aripiprazole substance with 15% acetonitrile (LiChrosolve^®, Merck, Darmstadt, Germany) and deionized water to a concentration of 500 µg/mL.

Animals

Male P-gp double knock-out mice on a FVB/N background [abcb1ab(−/−); Taconic, USA] and WT controls (also FVB/N background) both weighing 25–40 g were used for analysis. Mice were housed in groups of 2–5 with free access to food and water. A 12-h light-dark cycle was maintained (lights on from 6.00 a.m. until 6.00 p.m.) at a temperature of 22°C and a relative humidity of 60%. All experiments were conducted in accordance to the European Communities Council Directive of November 24^th 1986 (86/609/EEC) as well as Guidelines for the Care and Use of Mammals in Neuroscience and Behavioral Research” (National Research Council, 2003) and were approved by local authorities (based on the German Law for Protection of Animals).

Brain-serum ratios

For evaluation of P-gp substrate properties, aripiprazole (n=9) and ziprasidone (n=10) concentrations were determined in brain and serum. Brain to serum ratios between abcb1ab(−/−) and WT mice were calculated for 1 h after injection of 10 mg/kg aripiprazole or ziprasidone, in accordance with the method published by Doran et al. [5]. For aripiprazole analysis, brains were weighed and homogenized with 2 parts of 1-propanol (Carl Roth GmbH, Karlsruhe, Germany) and 2 parts deionized water, while for brain samples of ziprasidone 4 parts (vol/w) of methanol HPLC grade (Merck, Darmstadt, Germany) have been used. Homogenates were centrifuged (13 000 g; 5 min) and supernatants stored frozen (−20°C) until assayed. Blood samples were centrifuged (3 000 g; 10 min) and the resulting serum was collected. Ziprasidone and aripiprazole were analyzed using previously described high-performance liquid chromatography (HPLC) methods with pre-column clean-up and UV detection [18] [19].

RotaRod test

Mice were placed in a neutral position on a 3 cm diameter cylinder turning with a speed of 5 rounds per minute (rpm) (RotaRod Advanced, TSE Systems, Bad Homburg, Germany). After 10 seconds the speed was accelerated linearly up to 27.5 rpm within 240 s and time was taken automatically until the mice fell from the cylinder. With this procedure animals were trained 5 days before the test day to achieve comparable conditions of locomotor performance between mice. On the first day of training three trials and on the next 4 days four trials in each case were conducted [6] [17]. Thereby, control values were calculated for times that each mouse achieved at day 4 and 5 during training sessions (mean) on the RotaRod. Mean values of individual mice were used as baseline (100%), to minimize inter-individual variation, to which the means of 3 consecutive trials at each time point of testing day were related. In this way each mouse built a control to itself.

Drug application

On the following test day WT mice were given an i.p. injection of 1 (n=10), 5 (n=9), or 10 (n=5) mg/kg aripiprazole, or saline solution (n=17), P-gp abcb1ab(−/−) mice were similarly treated with doses of 1, 5 and 10 mg/kg aripiprazole (n=10, 9, 8 respectively), or saline solution (n=17). Animals were tested 0.5, 2, 4, 6, 8, 10, and 12 h after i.p. injection at all time points in 3 consecutive trials.

In the case of ziprasidone, abcb1ab(−/−) and WT mice were similarly treated with 1, 5, and 10 mg/kg [n=9, 10, 12 for WT and 10, 10, 11for abcb1ab(−/−), respectively] and tested on the RotaRod 0.5, 2, 4, 6, 8 h after injection. Later time points have been omitted, because performance after 8 h was already above 100% of the control value in both the abcb1ab(−/−) and the WT mice.

Application of haloperidol and serotonin receptor ligands

For evaluation of a differential role of dopamine- and serotonin-related neurotransmission affected by aripiprazole or ziprasidone, selective drugs were investigated on the RotaRod in WT mice. Buspirone (n=10), a 5-HT_1a agonist and ketanserin (n=10), a selective 5-HT₂ receptor antagonist, were used. In addition, haloperidol (n=10), a potent D₂ antagonist, was used. Doses used were 2.5 mg/kg for buspirone [20] and 3 mg/kg for ketanserin [21] and haloperidol [6]. As mentioned before, for intra-individual control values, the mice have been trained on the RotaRod for 5 days (see 2.4.). On day 6, locomotor performance was tested 0.5, 2, 4, 6, 8, 10 and 24 h after drug injection. To exclude possible effects of the vehicle, a control group (n=9) received vehicle (saline, containing 0.1% Tween 80 and 0.1% acetic acid) only.

Statistics

If possible, analysis of variance (ANOVA) was used for statistical analysis of dose and genotype effects followed by Student’s t-test with Bonferroni adjustation for multiple testing where appropriate. P-values of less than 0.05 were considered statistically significant. All statistical analyses were performed using IBM SPSS version 20.0.0 for Windows (SPSS Inc., Chicago, USA).

Results

To characterize P-gp substrate properties of aripiprazole and ziprasidone brain and serum concentrations were determined in abcb1ab(−/−) and WT mice. Ratios of brain to serum concentrations for KO to WT genotypes were considered as measures of P-gp activity [5]. Ratios above 2–3 point to a P-gp activity [5]. Aripiprazole exhibited moderate activity indicated by a ratio of 3.1. In case of ziprasidone the ratio was 1.9 which was significantly lower than for aripiprazole ([Fig. 1]).

To analyze the functional consequences of being a P-gp substrate, motor behaviour was tested on a RotaRod [17]. Comparison of both untreated genotypes revealed no differences in baseline performance ([Fig. 2]).

Aripiprazole affected motor behaviour of the 2 genotypes differentially. In WT mice all 3 doses of aripiprazole impaired performance up to 8 h (p<0.05, [Fig. 3a] and [Table 1a]). A 2-way ANOVA revealed significant effects for time (A) F_(6,222)=14.198 p<0.001 and for treatment (B) F_(3,37)=29.478 p<0.001 but not for AxB interaction F_(18,222)=1.099 n.s. ([Fig. 3a]). The overall effect size was larger after 5 and 10 mg/kg than after 1 mg/kg ([Fig. 3a]). Differences between WT mice treated with 1 mg/kg or 5 mg/kg were significant after 6 h and 8 h but between 1 and 10 mg/kg dosed mice only at the early time points of 0.5 h and 2 h (p<0.05; [Fig. 3a]) and between 5 and 10 mg/kg dosed mice only at 0.5 h no significant effects were significant (p<0.05, [Fig. 3a]). Univariate effects are shown in [Fig. 3a] and [Table 1a].

In abcb1ab(−/−) animals that had increased brain concentrations due to the absence of P-gp motor performance was impaired to a larger extent than in WT animals, and effects were similar for all three doses of 1–10 mg/kg during the 12 h observation period ([Fig. 3b]). The 2-way ANOVA revealed significant effects on time (A) F_(6;240)=20.007 p<0.001, according to treatment (B) F_(3;40)=41.136 p<0.001 and on AxB interaction F_(20;240)=2.377 p<0.01. Between different doses were no significant differences: univariate effects are shown in [Fig. 3b] and [Table 1a].

When treated with ziprasidone, WT and abcb1ab(−/−) mice behaved similarly ([Fig. 4]). Motor behaviour was impaired in a dose dependent manner during the early phase of observation. For WT mice treated with ziprasidone. The 2-way ANOVA revealed a significant effect over time (A) F_(4,176)=62.396 p<0.001 as well as over treatment (B) F_(3,44)=10.463 p<0.001 and on AxB interaction F_(12,176)=13.7 28 p<0.001. Significant results of univariate analysis for each time point is presented in [Fig. 4a] and [Table 1b]. All 3 doses of ziprasidone impaired performance 0.5 h after injection significantly (p<0.05, [Fig. 3a]). But only the dose of 10 mg/kg ziprasidone produced a significant deficit at 2 h and 4 h (p<0.05; [Fig. 4a]). Differences between treated WT mice were dose dependent: 1–5 mg/kg at 0.5 h, between 1 and 10 mg/kg up to 2 h, and between 5 or 10 mg/kg dosed mice at 2 h and 6 h post injection of ziprasidone (p<0.05, [Fig. 4a]).

In the case of ziprasidone treatment of abcb1ab(−/−) the 2-way ANOVA revealed significant effects on time (A) F_(4;176)=60.930 p<0.001, according to treatment (B) F_(3;44)=1 6.838 p<0.001 and on AxB interaction F_(12;176)=16.402 p<0.001. Univariate effects were indicated in [Fig. 4b] and [Table 1b]. Performance of ziprasidone treated abcb1ab(−/−) mice was under each dose at least at one time point significantly different compared to untreated abcb1ab(−/−) mice ([Fig. 4b]). Treatment with 10 mg/kg had the strongest effects on RotaRod performance at 2 h and 4 h post treatment. The dose and time dependent behavioural response pattern observed after injection of ziprasidone was very similar in the 2 genotypes ([Fig. 4]). Differences in RotaRod performance between genotypes were not significant at any time point tested.

To study the role of the different neurotransmitter receptor systems involved in aripiprazole- or ziprasidone-induced effects, the serotonin 5-HT₂ receptor antagonist ketanserine, the partial 5-HT_1A receptor agonist buspirone and the selective dopamine D₂ receptor antagonist haloperidol were applied to WT mice. Haloperidol had a long lasting effect by impairing motor performance ([Fig. 5]). The mice reached baseline control values 24 h after haloperidol injection. After injection of ketanserin (3 mg/kg) performance was slightly reduced at 0.5 h and then significantly enhanced ([Fig. 5]; [Table 1a]). Buspirone (2.5 mg/kg) improved performance on the RotaRod from 2 h after drug injection until the end of the observation period ([Fig. 5]; [Table 1a]).

Discussion

In this study we investigated the pharmacodynamic consequences of P-gp substrate properties of the atypical antipsychotics aripiprazole and ziprasidone. According to the pharmacokinetic profile aripiprazole exhibited moderate P-gp substrate properties, as brain to serum ratios between genotypes showed a 3.1-fold difference ([Fig. 1]). For ziprasidone substrate properties for P-gp were less pronounced as indicated by a respective ratio of 1.9 ([Fig. 1]). According to Doran and co-workers [5] aripiprazole exhibits a moderate to medium-sized effect. These authors suggested a minor impact of P-gp for drugs exhibiting a 2- to 3-fold difference between genotypes with regard to actions of CNS-active compounds. Although our analysis is limited to only one time point, according to this definition aripiprazole and ziprasidone were slightly above and below this range indicating possible differences for pharmacodynamics effects.

Pharmacodynamic consequences were investigated using RotaRod performance [17]. Under both, aripiprazole and ziprasidone, all mice exhibited impaired motor performance independent of P-gp expression. Motor impairment is typically associated with D2 receptor antagonism. This view was in line with our findings that aripiprazole and ziprasidone effects in WT animals were qualitatively similar to those of haloperidol but the intensity of action was less pronounced than for haloperidol. Less pronounced motor effects of aripiprazole or ziprasidone than of haloperidol might be due to differences in antidopaminergic properties. For aripiprazole it must be considered that it has also antihistaminergic effects which might contribut to early motor impairing effects [9].

For aripiprazole and its active metabolite dehydroaripiprazole it has been shown it acts in vivo as a functional agonist at pre-synaptic dopamine D₂ receptors and as an antagonist at post-synaptic D₂ receptors [22] [23] [24] [25] [26] [27] [28] [29]. Another reason could be attributed to the effects of aripiprazole and ziprasidone on serotonin receptors. 5-HT_1A receptor agonism and 5-HT₂ antagonism attenuate antipsychotic-induced catalepsy [30] [31] [32] [33] [34] [35] [36] [37]. This could be confirmed here, since 5-HT_1A agonism by buspirone or 5-HT_2A and 5-HT_2C antagonism by ketanserin enhanced locomotor activity on the RotaRod ([Fig. 5]).

With regard to P-gp properties a leftward shift of the dose-response curve was observed in abcb1ab(−/−) animals treated with aripiprazole ([Fig. 3]). This was not observed for ziprasidone-treated mice showing a strong dose dependent effect on RotaRod performance in both genotypes ([Fig. 4]). Genotype dependent differences in pharmacodynamic properties of aripiprazole and ziprasidone tested in vivo confirmed the theoretical suggestion of Doran and co-workers [5] that a functional relevance of P-gp properties requires a brain to plasma concentration ratio between genotypes of at least 2–3. Aripiprazole was above and ziprasidone below this threshold. This indicates that clinical outcomes to aripiprazole are associated with differences in the expression of P-gp. Single nucleotide polymorphisms (SNPs) in the ABCB1 gene have been shown to influence P-gp expression and result in differences in absorption and disposition of drugs [15] [38] [39]. Furthermore, it has been shown that some drugs may induce or inhibit P-gp function in vivo, in humans [40] as well as in rodents [41].

From our animal experiments it is concluded that in vivo effects of aripiprazole and ziprasidone are the result of actions on dopamine and serotonin receptors. For aripiprazole but not for ziprasidone the magnitude of actions depend on the expression of P-gp expression.

Conflict of Interest

The authors declare no conlicts of interest

Acknowledgements

The authors wish to thank Gabi Stroba and Anette Rieger-Gies for support during the HPLC analysis. The work was supported by the Deutsche Forschungsgemeinschaft (DFG Grant, Hi399/6-1) and a Ph.D. scholarship by Cusanuswerk-Bischöfliche Studienförderung (Bonn, Germany).

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Correspondence

• References

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