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

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.

Key words

antipsychotics - P-glycoprotein - knock-out - pharmacokinetics - pharmacodynamics

• References

• 1 Cordon-Cardo C, O’Brien JP, Casals D et al. Multidrug-resistance gene (P-glycoprotein) is expressed by endothelial cells at blood-brain barrier sites. Proc Natl Acad Sci USA 1989; 86: 695-698
• 2 Schinkel AH, Wagenaar E, Mol CA et al. P-glycoprotein in the blood-brain barrier of mice influences the brain penetration and pharmacological activity of many drugs. J Clin Invest 1996; 97: 2517-2524
• 3 Uhr M, Grauer MT, Holsboer F. Differential enhancement of antidepressant penetration into the brain in mice with abcb1ab (mdr1ab) P-glycoprotein gene disruption. Biol Psychiatry 2003; 54: 840-846
• 4 Wang JS, Zhu HJ, Donovan JL et al. Aripiprazole brain concentration is altered in P-glycoprotein deficient mice. Schizophr Res 2009; 110: 90-94
• 5 Doran A, Obach RS, Smith BJ et al. The impact of P-glycoprotein on the disposition of drugs targeted for indications of the central nervous system: Evaluation using the mdr1a/1b knockout mouse model. Drug Metab Dispos 2005; 33: 165-174
• 6 Kirschbaum KM, Henken S, Hiemke C et al. Pharmacodynamic consequences of P-glycoprotein-dependent pharmacokinetics of risperidone and haloperidol in mice. Behav Brain Res 2008; 188: 298-303
• 7 Kirschbaum KM, Uhr M, Holthoewer D et al. Pharmacokinetics of acute and sub-chronic aripiprazole in P-glycoprotein deficient mice. Neuropharmacol 2010; 59: 474-479
• 8 Jordan S, Koprivica V, Dunn R et al. In vivo effects of aripriprazole on cortical and striatal dopaminergic and serotonergic function. Eur J Pharmacol 2004; 483: 45-53
• 9 Burris KD, Molski TF, Xu C et al. Aripiprazole, a novel antipsychotic, is a high-affinity partial agonist at human dopamine D2 receptors. J Pharmacol Exp Ther 2002; 302: 381-389
• 10 McQuade R, Burris KD, Jordan S et al. Aripiprazole: a dopamine-serotonin system stabilizer. Int J Neuropsychopharmacol 2002; 5 (Suppl. 01) S176
• 11 Kane JM, Carson WH, Saha AR et al. Efficacy and safety of aripiprazole and haloperidol versus placebo in patients with schizophrenia and schizoaffective disorder. J Clin Psychiatry 2002; 63: 763-771
• 12 Nordquist RE, Risterucci C, Moreau JL et al. Effects of aripiprazole/OPC-14597 on motor activity, pharmacological models of psychosis, and brain activity in rats. Neuropharmacology 2008; 54: 405-16
• 13 Bozina N, Kuzman MR, Medved V et al. Associations between MDR1 gene polymorphisms and schizophrenia and therapeutic response to olanzapine in female schizophrenic patients. J Psychiatr Res 2008; 42: 89-97
• 14 Xing Q, Gao R, Li H et al. Polymorphisms of the ABCB1 gene are associated with the therapeutic response to risperidone in Chinese schizophrenia patients. Pharmacogenomics 2006; 7: 987-993
• 15 Vijayan NN, Mathew A, Balan S et al. Antipsychotic drug dosage and therapeutic response in schizophrenia is influenced by ABCB1 genotypes: a study from a south Indian perspective. Pharmacogenomics 2012; 13: 1119-1127
• 16 Kelly MA, Rubinstein M, Phillips TJ et al. Locomotor activity in D2 dopamine receptor-deficient mice is determined by gene dosage, genetic background, and developmental adaptations. J Neurosci 1998; 18: 3470-3479
• 17 Kirschbaum KM, Hiemke C, Schmitt U. Rotarod impairment: catalepsy-like screening test for antipsychotic side effects. Int J Neurosci 2009; 119: 1509-1522
• 18 Sachse J, Haerrter S, Hiemke C. Automated determination of ziprasidone by HPLC with column switching and spectrophotometric detection. Ther Drug Monit 2005; 27: 158-162
• 19 Kirschbaum KM, Müller MJ, Zernig G et al. Therapeutic monitoring of aripiprazole by HPLC with column-switching and spectrophotometric detection. Clin Chem 2005; 51: 1718-1721
• 20 Jadhav SA, Gaikwad RV, Gaonkar RK et al. Dose-dependent response of central dopaminergic systems to buspirone in mice. Indian J Exp Biol 2008; 46: 704-714
• 21 Popova NK, Amstislavskaya TG. 5-HT_2A and 5-HT_2C serotonin receptors differentially modulate mouse sexual arousal and the hypothalamo-pituitary-testicular response to the presence of a female. Neuroendocrinol 2002; 76: 28-34
• 22 Kikuchi T, Tottori K, Uwahodo Y et al. 7-(4-[4-(2,3-Dichlorophenyl)-1-piperazinyl]butyloxy)-3,4-dihydro-2(1H)-quinolinone (OPC-14597), a new putative antipsychotic drug with both presynaptic dopamine autoreceptor agonistic activity and postsynaptic D2 receptor antagonistic activity. J Pharmacol Exp Ther 1995; 274: 329-336
• 23 Fujikawa M, Nagashima M, Inoue T et al. Partial agonistic effects of OPC-14597, a potential antipsychotic agent, on yawning behavior in rats. Pharmacol Biochem Behav 1996; 53: 903-909
• 24 Inoue T, Domae M, Yamada K et al. Effects of the novel antipsychotic agent 7-(4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butyloxy)-3,4-dihydro-2(1H)-quinolinone (OPC-14597) on prolactin release from the rat anterior pituitary gland. J Pharmacol Exp Ther 1996; 277: 137-143
• 25 Lawler CP, Prioleau C, Lewis MM et al. Interactions of the novel antipsychotic aripiprazole (OPC-14597) with dopamine and serotonin receptor subtypes. Neuropsychopharmacology 1999; 20: 612-627
• 26 Semba J, Watanabe A, Kito S et al. Behavioural and neurochemical effects of OPC-14597, a novel antipsychotic drug, on dopaminergic mechanisms in rat brain. Neuropharmacology 1995; 34: 785-791
• 27 Shapiro DA, Renock S, Arrington E et al. Aripiprazole, a novel atypical antipsychotic drug with a unique and robust pharmacology. Neuropsychopharmacology 2003; 28: 1400-1411
• 28 Zocchi A, Fabbri D, Heidbreder CA. Aripiprazole increases dopamine but not noradrenaline and serotonin levels in the mouse prefrontal cortex. Neurosci Lett 2005; 387: 157-161
• 29 Nagasaka Y, Oda K, Iwatsubo T et al. Effects of aripiprazole and ist active metabolite dehydroaripiprazole on the activities of drug efflux transporters expressed both in the intestine and at the blood-brain barrier. Biopharm Drug Dispos 2012; 33: 304-315
• 30 Rasmusson AM, Goldstein LE, Deutch AY et al. 5-HT1a agonist ±8-OH-DPAT modulates basal and stress-induced changes in medial prefrontal cortical dopamine. Synapse 1994; 18: 218-224
• 31 Tanda G, Carboni E, Frau R et al. Increase of extracellular dopamine in the prefrontal cortex: a trait of drugs with antidepressant potential?. Psychopharmacology 1994; 115: 285-288
• 32 Hicks PB. The effect of serotonergic agents on haloperidol-induced catalepsy. Life Sci 1990; 47: 1609-1615
• 33 Broekkamp CL, Oosterloo SK, Berendsen HH et al. Effect of metergoline, fenfluramine, and 8-OHDPAT on catalepsy induced by haloperidol or morphine. Naunyn Schmiedebergs Arch Pharmacol 1988; 338: 191-195
• 34 Invernizzi RW, Cervo L, Samanin R. 8-Hydroxy-2-(di-n-propylamino) tetralin, a selective serotonin1A receptor agonist, blocks haloperidol-induced catalepsy by an action on raphe nuclei medianus and dorsalis. Neuropharmacology 1988; 27: 515-518
• 35 Kleven MS, Barret-Grevoz C, Bruins Slot L et al. Novel antipsychotic agents with 5-HT(1A) agonist properties: role of 5-HT(1A) receptor activation in attenuation of catalepsy induction in rats. Neuropharmacol 2005; 49: 135-143
• 36 Bardin L, Kleven MS, Barret-Grevoz C et al. Antipsychotic-like vs cataleptogenic actions in mice of novel antipsychotics having D₂ antagonist and 5-HT_1A agonist properties. Neuropsychopharmacol 2006; 31: 1869-1879
• 37 Bruins Slot LA, Kleven MS, Newman-Tancredi A. Effects of novel antipsychotics with mixed D₂ antagonist/5-HT_1A agonist properties on PCP-induced social interaction deficits in the rat. Neuropharmacol 2005; 49: 996-1006
• 38 Hoffmeyer S, Burk O, von Richter O et al. Functional polymorphisms of the human multidrugresistance gene: Multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo. Proc Natl Acad Sci USA 2000; 97: 3473-3478
• 39 Uhr M, Tontsch A, Namendorf C et al. Polymorphisms in the drug transporter gene ABCB1 predict antidepressant treatment response in depression. Neuron 2008; 57: 203-209
• 40 Nakagami T, Yasui-Furukori N, Saito M et al. Effect of verapamil on pharmacokinetics and pharmacodynamics of risperidone: In vivo evidence of involvement of P-glycoprotein in risperidone disposition. Clin Pharmacol Ther 2005; 78: 43-51
• 41 Holthoewer D, Hiemke C, Schmitt U. Induction of drug transporters alters disposition of risperidone – a study in mice. Pharmaceutics 2010; 2: 258-274