Studies on the Acute Toxicity, Pharmacokinetics and Pharmacodynamics of Paliperidone Derivatives – Comparison to Paliperidone and Risperidone in Mice and Rats

Abstract

The objective of this study was to investigate the acute toxicity, pharmacokinetics and pharmacodynamics of paliperidone derivatives (PDs) compared with paliperidone and risperidone. The i.g. LD 50 and i.v. maximum tolerated doses of PD1, PD5 and PD6 were greater than those of paliperidone and risperidone in mice. Pharmacokinetic study showed that PDs were quickly metabolized to paliperidone to take effect in the treatment of schizophrenia in rats after i.g. administration. Only traces of the parent substances were found. Pharmacodynamic study showed that PDs significantly reduced MK-801-induced hyperlocomotion in mice. The electrocardiogram (ECG) was recorded at 0,5,10,15,20, 25, 30, 45 and 60 min. in anaesthetized rats after i.v. injection of 0.21, 0.59, 1.69 lmol ⁄ kg drugs. Heart rate reduction had a linear relation with dose after i.v. injection of PDs, paliperidone and risperidone. No significant change in the ECG parameters was found in all groups after administration of the low dose. Although the reductions in heart rate and the corrected QT interval (QTc) were observed in all drugs at the high dose, PD5 and PD6 were associated with smaller effects on the ECG parameters than other compounds, including paliperidone and risperidone. Therefore, PD5 and PD6 could be potential candidates for the treatment of schizophrenia.Risperidone, 3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidin]ethyl}-6,7,8,9-tetrahydro-2-methyl-4H-pyrido-[1,2-a]py rimidine-4-one, is a serotonin 5-HT 2 and dopamine D 2 receptor antagonist and widely used in the treatment of schizophrenia as an atypical antipsychotic drug. In human beings, risperidone is mainly metabolized to 9-hydroxyrisperidone by cytochrome P450 in the liver [1]. Because of its antipsychotic activity, 9-hydroxyrisperidone has been reported under the name of paliperidone for the treatment of schizophrenia. Johnson and Johnson launched paliperidone under the trade name of Invega in the end of 2006. The poor absolute oral bioavailability (only 28%) and the high daily dose of Invega may lead to an increased risk of side effects [2]. Consequently, it is very important to search for new derivatives of paliperidone for the treatment of schizophrenia with higher oral bioavailability and lower side effects [3]. A series of paliperidone derivatives (PDs) were synthesized ( fig. 1) and their physical and chemical properties are listed in table 1.Among patients with schizophrenia, accelerated heart disease is a major cause of sudden death and the risk of dying from cardiovascular disease is two to three times higher than in the general population [4]. Numerous antipsychotic drugs are well-documented for their effects on the QT interval [5]. Prolongation of the QT interval by risperidone has also been reported in a clinical study [6]. In vitro electrophysiological studies showed that supra-therapeutic doses of risperidone induced the prolongation of ventricular repolarization in a dose-related and reverse use-dependent manner, which prolonged the terminal repolariza...

Paliperidone extended-release: does it have a place in antipsychotic therapy?

“…A study by Sun et al72 investigated the acute toxicity of PER and its derivatives in mice and rats. To maintain a comprehensive view on the safety and tolerability of PER in human subjects and patients, we reviewed the adverse side effects that occurred in the published efficacy studies of Marder et al, Kane et al, Davidson et al,44–46 and the symptom recurrence study by Kramer 61.…”

“…Sun et al72 investigated the acute toxicity of risperidone, PER, and its derivatives in mice and rats. They found a LD 50 of 50.89 mg/kg body weight for risperidone and 162.65 mg/kg for PER.…”

Physiologically Based Modeling Approach to Predict Dopamine D2 Receptor Occupancy of Antipsychotics in Brain: Translation From Rat to Human

“…The model adequately predicted the plasma PK of clozapine and norclozapine (following norclozapine administration as well as metabolite formed following clozapine administration) (Figure A) and risperidone and its metabolite paliperidone (following paliperidone administration as well as metabolite formed following risperidone administration) (Figure B). Nevertheless, the model underestimated the relatively high paliperidone plasma concentrations observed in the study of Sun et al in which a high IV bolus dose of paliperidone was administered. Noteworthy is that in the rat PBPK model linear, nonsaturable clearance in liver and kidney was applied to all compounds due to a lack of information about the enzyme kinetics in rats.…”

Proteinoid Nanocapsules as Drug Delivery System for Improving Antipsychotic Activity of Risperidone

“…These opposing parameters influence the bioavailability of RSP and therefore should be taken into consideration [ 5 ]. Hydroxylation is also related to the generic polymorphism of RSP [ 6 ]. The polymorphism of the CYP2D6 gene has an important part in RSP metabolism when expressed in the blood, and demonstrates that RSP is poorly water-soluble, a weak base, and an unstable molecule.…”