Disease relevance of R 76477

• The Css values of risperidone and 9-hydroxyrisperidone were corrected to the median body weight of 58 kg [1].

Psychiatry related information on R 76477

• SUMMARY: The effects of paroxetine on steady-state plasma concentrations of risperidone and its active metabolite 9-hydroxyrisperidone (9-OH-risperidone) were studied in 10 patients with schizophrenia or schizoaffective disorder [2].
• The effect of fluvoxamine on plasma concentrations of risperidone and its active metabolite 9-hydroxyrisperidone (9-OH-risperidone) was investigated in 11 schizophrenic patients with prevailingly negative or depressive symptoms [3].

High impact information on R 76477

• However, the ratio of risperidone/9-hydroxyrisperidone, an index of CYP2D6 activity, did not differ before itraconazole treatment (0.14 +/- 0.13), after itraconazole treatment (0.15 +/- 0.13), and 1 week after discontinuation (0.14 +/- 0.13) (P > .05) [4].
• Plasma concentrations of risperidone, 9-hydroxyrisperidone, and prolactin were monitored up to 24 hours after dosing [5].
• The pharmacokinetics of the active moiety (risperidone plus 9-hydroxyrisperidone) varied little among subjects (mean terminal half-life, 20 +/- 2 1/2 hours; absolute oral and intramuscular bioavailability, 100%) [6].
• Plasma concentrations of risperidone and 9-hydroxyrisperidone were quantified with liquid chromatography-mass spectrometry mass-mass spectrometry together with clinical assessments before and after each phase of the 3 paroxetine doses [7].
• Baseline separation and structure elucidation of two clinically interesting basic drugs, risperidone and 9-hydroxyrisperidone, are achieved by coupling pressure-assisted CE to ESI-TOFMS using the described sheathless electrospray emitter with a bare fused-silica capillary at pH 6 [8].

Biological context of R 76477

• Cytochrome P450 2D6 genotype and steady state plasma levels of risperidone and 9-hydroxyrisperidone [9].
• The 90% confidence intervals for the i.m./oral ratios of the mean steady-state plasma-AUC, corrected for dosing interval, and of the average plasma concentration of the active moiety (risperidone plus 9-hydroxyrisperidone) were within the range of 80-125%, indicating bioequivalence of the i.m. and oral formulations [10].
• No significant changes occurred between treatments in the area under the concentration-time curve (AUC) for 9-hydroxyrisperidone or the total active moiety [11].

Anatomical context of R 76477

• As risperidone is more lipophilic and less effluxed by P-glycoprotein in the blood-brain-barrier than the active metabolite 9-hydroxyrisperidone, one might speculate that patients with high plasma metabolite/drug ratios obtain lower active concentrations in the brain [12].
• A correlation study using a panel of human liver microsomes showed that the formation of 9-hydroxyrisperidone is highly correlated with CYP2D6 and 3A activities [13].
• Transfer of risperidone and 9-hydroxyrisperidone into human milk [14].

Associations of R 76477 with other chemical compounds

• In vitro, risperidone and 9-hydroxyrisperidone had similar binding profiles, and their highest affinity was for 5-HT2A receptors (cloned human, Ki 0.4 nM); affinities for other 5-HT-receptor subtypes were at least 100 times lower [15].
• In contrast, the ratio of prolactin concentration to nmol/l unit drug concentration (the active moiety: the sum of risperidone and 9-hydroxyrisperidone) during risperidone treatment (median 1.10, range 0.02-3.73) was significantly lower ( P<0.001) than that of haloperidol (median 1.81, range 0.41-8.24) [16].
• The treatment ratios of AUC and associated 90% confidence intervals (CIs) for risperidone active moiety, defined as risperidone plus 9-hydroxyrisperidone (ratio = 110.2%; 90% CI = 103.7-117.2), and for donepezil (ratio = 97.1%; 90% CI = 90.0-103.6) were within the 80% to 125% of bioequivalence range [17].
• The formation of 9-hydroxyrisperidone is highly correlated with testosterone 6beta-hydroxylase activities, suggesting that inducible CYP3A contributes significantly to the metabolism of risperidone in rat [13].
• The enantiomers of 9-hydroxyrisperidone were analyzed with high pressure liquid chromatography using a chiral alpha-1 acid glycoprotein column [18].
• Regarding the critical comparison of oral paliperidone to risperidone, we have no information and are thus unable to determine if paliperidone has any advantages or disadvantages compared to its well-known parent compound [19].

Gene context of R 76477

• This observation is confirmed by the findings that both quinidine (inhibitor of CYP2D6) and ketoconazole (inhibitor of CYP3A4) can inhibit the formation of 9-hydroxyrisperidone [13].
• Metabolism of risperidone to 9-hydroxyrisperidone by human cytochromes P450 2D6 and 3A4 [13].
• The binding affinity of risperidone and 9-hydroxyrisperidone for the D2 family of receptors (D2L, D2S, D3, D4) was one order of magnitude lower than their affinity for 5-HT2A receptors [15].
• Furthermore, inducers of CYP can significantly increase the formation of 9-hydroxyrisperidone in rat [13].
• CONCLUSIONS: These findings suggest that the MDR-1 variants are not associated with steady-state plasma concentration of risperidone or 9-hydroxyrisperidone, but CYP2D6 genotypes and age are determinants of these concentrations [20].

Analytical, diagnostic and therapeutic context of R 76477

• Endpoint steady-state plasma levels of risperidone and 9-hydroxyrisperidone were analyzed by high performance liquid chromatography with ultraviolet detection [21].
• The primary efficacy variable was the time of first recurrence of schizophrenia symptoms, which included predefined changes in symptom scores, psychiatric hospitalization, self-injury, and suicidal or aggressive behavior during the double-blind phase (paliperidone ER or placebo treatment) [22].
• In this randomized, double-blind, placebo-controlled, multicenter study, patients' symptoms were stabilized during an 8-week run-in and a 6-week stabilization phases using open-label, flexibly dosed paliperidone ER (3-15 mg once daily, starting dose = 9 mg) [22].
• The interaction of risperidone, 9-hydroxyrisperidone (the principal active metabolite), and clozapine with neurotransmitter receptors was investigated in vitro using animal brain tissue homogenates and cloned human receptors expressed in cells and ex vivo using quantitative receptor autoradiography in rat and guinea pig brain sections [15].
• The patients received risperidone orally (dose range, 0.5-11 mg per day) and had concentrations of risperidone and the active metabolite 9-hydroxyrisperidone measured at steady state by a new, rapid, and sensitive method of high-performance liquid chromatography (HPLC) [23].

References