The Pharmacological Role and Clinical Applications of Antipsychotics’ Active Metabolites: Paliperidone versus Risperidone

López‐Muñoz, Francisco; González, Cristerna

doi:10.4172/2161-1459.1000117

Cited by 30 publications

(29 citation statements)

References 106 publications

(140 reference statements)

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“…The 0.75 mg/kg dose was based on preliminary pharmacokinetic studies that evaluated plasma drug concentrations (total drug) after administration of various doses of RIS ( Figure 3 and our unpublished data). The dose of 0.75 mg/kg produced peak serum levels of RIS and the active metabolite, PAL, most similar to those achieved in patients (33). The issue of dose selection/ optimization remains a problem with rodent models for testing for off-target antipsychotic complications due to the inability of lower doses to induce weight gain.…”

Section: Discussionmentioning

confidence: 84%

“…The dose of RIS was chosen based on preliminary pharmacokinetic studies that evaluated plasma drug concentrations (total drug) after administration of various doses of RIS by oral gavage (K.J.M., D.B., K.L.H., unpublished data). The dose of 0.75 mg/kg produced peak serum levels of RIS and the active metabolite, paliperidone (PAL), most similar to that achieved in patients (33). A subset of mice were treated with vehicle or RIS as above for 2 weeks and then placed in metabolic cages.…”

Section: Mice: Ris and Ris ؉ Pro Studiesmentioning

confidence: 99%

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Propranolol Attenuates Risperidone-Induced Trabecular Bone Loss in Female Mice

et al. 2015

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Atypical antipsychotic (AA) drugs cause significant metabolic side effects, and clinical data are emerging that demonstrate increased fracture risk and bone loss after treatment with the AA, risperidone (RIS). The pharmacology underlying the adverse effects on bone is unknown. However, RIS action in the central nervous system could be responsible because the sympathetic nervous system (SNS) is known to uncouple bone remodeling. RIS treatment in mice significantly lowered trabecular bone volume fraction (bone volume/total volume), owing to increased osteoclast-mediated erosion and reduced osteoblast-mediated bone formation. Daytime energy expenditure was also increased and was temporally associated with the plasma concentration of RIS. Even a single dose of RIS transiently elevated expression of brown adipose tissue markers of SNS activity and thermogenesis, Pgc1a and Ucp1. Rankl, an osteoclast recruitment factor regulated by the SNS, was also increased 1 hour after a single dose of RIS. Thus, we inferred that bone loss from RIS was regulated, at least in part, by the SNS. To test this, we administered RIS or vehicle to mice that were also receiving the nonselective β-blocker propranolol. Strikingly, RIS did not cause any changes in trabecular bone volume/total volume, erosion, or formation while propranolol was present. Furthermore, β2-adrenergic receptor null (Adrb2(-/-)) mice were also protected from RIS-induced bone loss. This is the first report to demonstrate SNS-mediated bone loss from any AA. Because AA medications are widely prescribed, especially to young adults, clinical studies are needed to assess whether β-blockers will prevent bone loss in this vulnerable population.

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Section: Discussionmentioning

confidence: 84%

Section: Mice: Ris and Ris ؉ Pro Studiesmentioning

confidence: 99%

Propranolol Attenuates Risperidone-Induced Trabecular Bone Loss in Female Mice

et al. 2015

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“…In addition, it is used off-label in the treatment of ADHD in children. The metabolism of risperidone is stereoselectively catalyzed (i) by CYP2D6 at the aliphatic heterocycle to give the major enantiomer (+)-9-hydroxyrisperidone, and (ii) by CYP3A4 to (−)-9-hydroxyrisperidone ( Figure 17) [49][50][51][52][53]. Both enantiomers are equiactive with risperidone and have been developed into the racemate antipsychotic drug paliperidone [49][50][51][52][53].…”

Section: Risperidone/paliperidonementioning

confidence: 99%

Metabolic-Hydroxy and Carboxy Functionalization of Alkyl Moieties in Drug Molecules: Prediction of Structure Influence and Pharmacologic Activity

El‐Haj

Ahmed

2020

Molecules

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Alkyl moieties—open chain or cyclic, linear, or branched—are common in drug molecules. The hydrophobicity of alkyl moieties in drug molecules is modified by metabolic hydroxy functionalization via free-radical intermediates to give primary, secondary, or tertiary alcohols depending on the class of the substrate carbon. The hydroxymethyl groups resulting from the functionalization of methyl groups are mostly oxidized further to carboxyl groups to give carboxy metabolites. As observed from the surveyed cases in this review, hydroxy functionalization leads to loss, attenuation, or retention of pharmacologic activity with respect to the parent drug. On the other hand, carboxy functionalization leads to a loss of activity with the exception of only a few cases in which activity is retained. The exceptions are those groups in which the carboxy functionalization occurs at a position distant from a well-defined primary pharmacophore. Some hydroxy metabolites, which are equiactive with their parent drugs, have been developed into ester prodrugs while carboxy metabolites, which are equiactive to their parent drugs, have been developed into drugs as per se. In this review, we present and discuss the above state of affairs for a variety of drug classes, using selected drug members to show the effect on pharmacologic activity as well as dependence of the metabolic change on drug molecular structure. The review provides a basis for informed predictions of (i) structural features required for metabolic hydroxy and carboxy functionalization of alkyl moieties in existing or planned small drug molecules, and (ii) pharmacologic activity of the metabolites resulting from hydroxy and/or carboxy functionalization of alkyl moieties.

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“…When risperidone is administered, its pharmacological effects are due to the original molecule as well as its active metabolite. Considering that many patients who take risperidone orally exhibit plasma levels of 9-OH-risperidone 5–10 times higher than risperidone (34), we consider the metabolite to play an important role in the antipsychotic’s antidepressant effect (Table 2) (35). In fact, extended-release paliperidone, whether taken orally (36) or as an injection (37), has proven effective in treating schizoaffective disorder, a profile marked by a set of schizophrenia symptoms in addition to major depressive disorder.…”

Section: Active Metabolites Of Atypical Antipsychotic Drugs With Antimentioning

confidence: 99%

Active Metabolites as Antidepressant Drugs: The Role of Norquetiapine in the Mechanism of Action of Quetiapine in the Treatment of Mood Disorders

López‐Muñoz

Álamo

2013

Front. Psychiatry

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Active metabolites of some antipsychotic drugs exhibit pharmacodynamic and pharmacokinetic properties that may be similar to or differ from the original compound and that can be translated by a different profile of responses and interactions to clinical level. Some of these antipsychotics’ active metabolites might participate in mechanisms of antidepressant activity, as m-chlorophenylpiperazine (aripiprazole), 9-OH-risperidone and norquetiapine. Norquetiapine exhibits distinct pharmacological activity from quetiapine and plays a fundamental role in its antidepressant efficacy. In this review, we analyze the differential pharmacological aspects between quetiapine and norquetiapine, both from the pharmacokinetic and pharmacodynamic perspectives (affinity for dopaminergic, noradrenegic, and/or serotonergic receptors, etc.), as well as differential neuroprotective role. The pharmacological differences between the two drugs could explain the differential clinical effect, as well as some differences in tolerability profile and drug interactions. The available data are sufficient to arrive at the conclusion that antidepressant activity of quetiapine is mediated, at least in part, by the active metabolite norquetiapine, which selectively inhibits noradrenaline reuptake, is a partial 5-HT1A receptor agonist, and acts as an antagonist at presynaptic α2, 5-HT2C, and 5-HT7 receptors.

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The Pharmacological Role and Clinical Applications of Antipsychotics’ Active Metabolites: Paliperidone versus Risperidone

Cited by 30 publications

References 106 publications

Propranolol Attenuates Risperidone-Induced Trabecular Bone Loss in Female Mice

Propranolol Attenuates Risperidone-Induced Trabecular Bone Loss in Female Mice

Metabolic-Hydroxy and Carboxy Functionalization of Alkyl Moieties in Drug Molecules: Prediction of Structure Influence and Pharmacologic Activity

Active Metabolites as Antidepressant Drugs: The Role of Norquetiapine in the Mechanism of Action of Quetiapine in the Treatment of Mood Disorders

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