Risperidone, metabolite

Risperidone and its active metabolite 9-OH-resperidone are metabolized by CYP2D6. Polymorphic metabolism should be considered in those with side effects at low doses (approximately 40% of African Americans and Asians can have increased side effects from risperidone and other drugs metabolized through CYP2D6). 

Recently, three papers have reported the determination of risperidone and its active metabolite 9-hydroxyrisperidone using LLE and SPE technologies. The analytical columns used to separate these compounds were C4 or C18 bonded phases of 3 pm or 5 pm particle sizes with UV/VIS detection. Mobile phases consisted of phosphate bufiers (pH 3-4) in acetonitrile. The sample volumes used ranged from 200 pi to 1 ml, with extraction recoveries averaging 90%. The limits of quantitation ranged from 0.5 to 10 ng/ml in human plasma (Nagasaki et al., 1999 Avenso et al., 2000 Titier et al., 2002). A study by Titier showed the simultaneous determination of clozapine, olanzapine, haloperidol, risperidone, and its active metabolites by RP-HPLC in human plasma. The assay involved LLE with a hexane/isoamyl alcohol mixture... 

Avenso A, Facciola G, Salemi M, Spina E. 2000. Determination of risperidone and its major metabolite 9-hydroxyris-peridone in human plasma by reversed-phase liquid chromatography with ultraviolet detection. J Chromatogr B Biomed Sci Appl 746(2) 173-181. 

Exogenous Chemicals Neuroleptics Risperidone and its metabolites Moody et al. (2004)... 

Receptor-Binding Studies. Risperidone (Risperdal) is a benzisoxazole derivative that has a relatively high 5-HT " tio and relatively fewer and milder EPS than neuroleptics at its clinically effective doses. Receptor-binding studies of risperidone and its active metabolite, 9-OH-risperidone, in comparison with other novel antipsychotics revealed that ... 

Case Example Because of a patient s partial response to 5 months of clozapine therapy at 600 mg/day, risperidone was added for augmentation (started with 0.5 mg b.i.d. and increased to 1 mg b.i.d. after 1 week). Before this addition, the clozapine plasma level was 344 ng/mL, but after 2 weeks of risperidone augmentation, the level was elevated to 598 ng/mL with no adverse effects and substantial clinical benefit. In another report, there was an increase in the steady-state plasma levels of clozapine (675 mg/day) and its active metabolite norclozapine after the addition of risperidone 2 mg/day in a patient treated for 2 years. Before the addition of risperidone, her clozapine and norclozapine levels were 829 and 1,384 ng/mL, respectively. Two days after risperidone was added, these levels rose to 980 and 1,800 ng/mL. Clozapine dosage was reduced to 500 mg/day, and after 5 days of combined treatment with 4 mg/day of risperidone, the clozapine and norclozapine levels were 110 and 760 ng/mL, respectively. Aside from some mild oculogyric crises, she had no symptoms of clozapine toxicity or clinical changes during the period of cross-tapering. In another case, risperidone was added to clozapine because the patient had relapsed after discontinuation of fluphenazine and had not responded to clozapine. The addition of risperidone resulted in an acute remission of psychosis ( 100). 

Another cytochrome P450 enzyme of importance to atypical antipsychotic drugs is 2D6. Risperidone, clozapine, and olanzapine are all substrates for this enzyme (Fig. 11—46). Risperidone s metabolite is also an active atypical antipsychotic (Fig. 11 — 47), but the metabolites of clozapine and olanzapine are not. Recall that some antidepressants are inhibitors of CYP450 2D6 and thus can raise the levels of these... 

FIGURE 11-47. Risperidone is converted to an active metabolite by the enzyme CYP450 2D6. 

Until approximately a decade ago, gas chromatography mass spectrometry (GC-MS) was considered the gold standard of analysis and quantification of drugs and their metabolites in biological matrices [26], In order to be suitable for GC-analysis, a compound needs to be volatile and thermally stable to such an extent that it can be transferred into a gas phase. Unfortunately, several APs, such as risperidone are unstable and are not amenable to direct GC analysis due to their chemical properties. In addition, standard GC-MS instruments do often not provide sufficient sensitivity to detect the low concentrations in which certain... 

Bhatt J, Subbaiah G, Singh S (2006) Liquid chromatography/tandem mass spectrometry method for simultaneous determination of risperidone and its active metabolite 9-hydroxyris-peridone in human plasma. Rapid Commun Mass Spectrom 20(14) 2109—2114. doi 10.1002/ rcm.2537... 

Szulc A, Galinska B, Tarasow E, Dzienis W, Kubas B, et al. 2005. The effect of risperidone on metabolite measures in the frontal lobe, temporal lobe, and thalamus in schizophrenic patients. A proton magnetic resonance spectroscopy (lh mrs). Pharmacopsychiatry 38 214-219. 

SSRIs are often prescribed with antipsychotic drugs, and some SSRIs inhibit CYP2D6, which can lead to increased blood concentrations of the antipsychotic drug. In 13 patients aged 26-56 years with schizophrenia, stabilized on risperidone 4-6 mg/day who took sertraline 50 mg/day for 4 weeks, plasma concentrations of risperidone and its major metabolite, 9-OH-risperidone, did not change... 

Avenoso A, Facciola G, Scordo MG, Gitto C, Ferrante GD. No effect of citalopram on plasma levels of clozapine, risperidone and their active metabolites in patients with chronic schizophrenia. Clin Drug Invest 1998 16 393-8. 

The addition of paroxetine 20 mg/day to risperidone 4-8 mg/day in 10 patients with schizophrenia produced a 45% increase in plasma concentrations of risperidone and its active metabolite, 9-hydroxyrisperidone (30). 

A 40-year-old man had taken clozapine 450 mg/day and risperidone 6 mg/day for several years. Nefazodone 200 mg/day was added in an attempt to improve persistent negative symptoms, and after a week the dosage was increased to 300 mg/day. One week later, he reported anxiety and dizziness and was hypotensive. The combined concentrations of clozapine and its active metabolite norclozapine had increased from 309 ng/ml before nefazodone to 566 ng/ml. The nefazodone dosage was reduced to 200 mg/day and the anxiety, dizziness, and hypotension resolved over the next 7 days. At the same time plasma concentrations of clozapine and norclozapine fell to 370 ng/ml. 

Citalopram had no effect on plasma concentrations of clozapine (n = 8), risperidone (n = 7), or their active metabolites over 8 weeks (263). However, a possible interaction of clozapine with citalopram has been reported, with increased serum clozapine concentrations, perhaps dose-related (264). 

The transfer to milk of risperidone and its active metabolite 9-hydroxyrisperidone has been examined in two breast-feeding women and in one woman with risperidone-induced galactorrhea (209). The milkrplasma concentration ratio was under 0.5 for both compounds the calculated relative infant doses were 2.3%, 2.8%, and 4.7% of that of women s weight-adjusted doses neither compound was detected in the plasma of the two babies, who achieved their developmental milestones satisfactorily and did not have any adverse effect attributable to risperidone. The authors concluded that maternal risperidone therapy is unlikely to pose a significant hazard to the breast-fed infant in the short term, and recommended an individual benefit-harm analysis to take decisions about this issue. 

A homozygous non-functional genotype, CYP2D6 4, was found in a 17-year-old patient with schizophrenia who developed severe akathisia, parkinsonism, and drowsiness after taking risperidone 6 mg/day for 3 months he had high plasma concentrations of risperidone and an active metabolite (210). 

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