Research report
Pharmacodynamic consequences of P-glycoprotein-dependent pharmacokinetics of risperidone and haloperidol in mice

https://doi.org/10.1016/j.bbr.2007.11.009Get rights and content

Abstract

Efflux transporters, like P-glycoprotein (P-gp), may limit the access of drugs to the brain via the blood–brain barrier. The antipsychotic drug risperidone and its active metabolite 9-hydroxyrisperidone (paliperidone) are substrates of P-gp. Motor behavior of P-gp deficient mice (mdr1a/1b (−/−, −/−)) and wild type animals on a rotarod after acute doses of risperidone or haloperidol, a nonsubstrate of P-gp, were analysed aiming to show that P-gp substrate properties of an antipsychotic drug have functional consequences. Behavioral tests revealed dose-dependent effects of 0.3–3 mg/kg risperidone in wild type animals 0.5–12 h after i.p. injection of the drug. In knockout mice the 0.3 mg/kg dose of risperidone was as effective as the 3 mg/kg dose in wild type mice. A dose of 0.3 mg/kg haloperidol, however, exhibited similar pharmacodynamic effects in both genotypes. Brain concentrations of risperidone plus 9-hydroxyrisperidone were 10-fold higher in knockout than in wild type animals whereas brain concentrations of haloperidol did not differ between the two genotypes. P-gp-dependent brain distribution kinetics and behavioral effects of risperidone give evidence that the expression of P-gp has an impact on psychotropic drug actions when treating patients with drugs that are substrates of P-gp.

Introduction

Pharmacokinetic peculiarities of individual patients due to variations in absorption, distribution, metabolism, or elimination of drugs can lead to safety or efficacy problems. One contributing factor is the passage through the blood–brain barrier. It is regulated by various efflux transport proteins. P-glycoprotein (P-gp), a member of the ATP-binding cassette superfamily (ABC family), plays an important role as an efflux pump for many drugs. It is encoded by the MDR1 gene in humans and the mdr1a (also named abcb1a or mdr3) and the mdr1b (also named abcb1b of mdr1) gene in mice [7], suggesting that mdr1a and mdr1b together fulfil the same function as MDR1 in human. P-gp is expressed in the luminal epithelial cells of organs often associated with drug absorption and disposition, for example, hepatocyte canalicular membrane, renal proximal tubules, and the intestinal mucosa [21]. P-gp is also localized in the endothelial cells comprising the blood–brain barrier [6]. This clearly suggests its potential to serve as a protective mechanism against the entry of xenobiotics, including therapeutic agents.

In vitro assays [1], [3], [25], [26], [29] and in vivo models [8], [19], [22], [24] especially mdr1a knockout [9], [18] or mdr1a/1b double knockout mice [20], identified psychoactive drugs as substrates or inhibitors of P-gp. An ATPase activity assay displayed high affinity of the antipsychotic risperidone for P-gp [3]. In vivo studies in mice [8], [9], [24] and in humans [16] revealed differences in brain and serum concentrations not only for risperidone but also for its active metabolite 9-hydroxyrisperidone which was recently approved as the new antipsychotic drug paliperidone and which has similar pharmacological activity as the parent-compound [9], [12]. Risperidone and its metabolite have both high affinity for serotonin 5-HT2 and moderate affinity for dopamine D2 receptors [15], [23]. In contrast, the conventional antipsychotic haloperidol with high antagonistic properties at the D2-receptor is a poor substrate of P-gp according to in vitro [3], [19] and in vivo studies [8], [9].

If P-gp substrate properties have consequences on the pharmacodynamics is best investigated by behavioural analysis. So far, to our knowledge, the latter has not been studied for psychoactive drugs. Behavioural changes in the mdr1a/b knockout mice in comparison to wild type animals enable to investigate whether P-gp-dependent differences in the expression level of the central nervous system (CNS) leads to functional dispositions. Motor impairment on a rotarod task is characteristic for antipsychotic-related D2-receptor antagonism [13]. This paradigm was applied in mdr1a/1b (−/−, −/−) (FVB-background) and FVB wild type (WT) mice after administration of either the known substrate risperidone or the at most poor substrate haloperidol. Brain and serum concentrations of both drugs as well as 9-hydroxyrisperidone were also studied between genotypes to confirm the magnitude of functional consequences with pharmacokinetic data in the same mice.

Section snippets

Drugs

Risperidone (Risperdal® solution) and haloperidol (Haldol-Janssen® solution) (both Janssen-Cilag GmbH, Neuss, Germany) were mixed with physiological saline for intra-peritoneal injections of mice. Solutions were administered in a total volume of 1 ml in concentrations of 0.3, 1, or 3 mg/kg risperidone or haloperidol, respectively.

Risperidone used for HPLC analysis was purchased from MP Biomedicals (Illkirch, France), 9-hydroxyrisperidone and haloperidol were kindly supplied by Janssen-Cilag

Results

Motor impairment, typically induced by central D2-receptor antagonism, was analyzed on the rotarod to investigate functional differences of the P-gp substrates risperidone and its metabolite and the nonsubstates haloperidol. Mdr1a/1b (−/−, −/−) mice treated with 0.3 mg/kg of the atypical antipsychotic risperidone showed different abilities in walking on the rotarod to equally treated WT mice. ANOVA revealed significant effects for genotype [F(1;22) = 43.812, p < 0.001], time [F(6;132) = 31.290, p < 

Discussion

The results of this study revealed a markedly different profile in centrally induced motor effects by the antipsychotic drug risperidone dependent on P-gp expression in mice. The similar performance for the first 6 h of mdr1a/1b (−/−, −/−) mice treated with 0.3 mg/kg and WT mice given a dose of 3 mg/kg risperidone revealed a factor of 10 in dose response. After that time even more impaired motor abilities of knockout animals of only 57% compared to WT animals were observed. This represents a

Acknowledgements

We would like to thank Dianne Lee for correction of the English language of the manuscript and Janssen-Cilag (Beerse, Belgium) for kindly supplying us with 9-hydroxyrisperidone pure drug substance.

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