Risperidone 9-hydroxy

In another study [45], the quantitation of risperidone and its 9-hydroxy metabolite in EDTA-anticoagulated plasma was reported. After protein precipitation with acetorritrile, the superrratant was injected onto an on-line SPE-LC-MS system. The sample was loaded in a weak solvent (15% acetorritrile in 10 rmnol/1 aqueous AmOAc) to a 12.5x4.6-mm-ID Cig SPE-colurrm (5 pm) for 1 min at 0.7 rtil/min. After valve-switching, the SPE colurtm was backflushed with a stronger solvent (80% acetonitrile in 10 mmoFl aqueous AmOAc) to the 30x2.1-mm-ID Cig analytical colurrm (3.5 pm) at 0.35 ml/min. Positive-ion ESI-MS was applied in SRM mode, monitoring transitions for risperidone, 9-hydroxy risperidone, and an ANIS. No separation of the 7-hydroxy and 9-hydroxy metabolites was achieved under these conditions. The method was validated. 

Stability constants of metal complexes of 9-hydroxy-4//-pyrido[l,2-n]pyrimidin-4-one [Ni(II), Co(II), Zn(II), and Cd(II)] were determined by potentiometric and polarographic investigations (93JCC283). The distribution coefficient of risperidone (11) in H20- -octanol at pH 7.4 (log D — 2.04) was determined by an RP-HPLC method (01JMC2490). 

The octanol-water (pH 5) partition coefficients of alkyl-substituted 4H-pyrido[l,2-a]pyrimidines-4-ones 10 and 11, 3-phenyl and 3-ester derivatives (R2 = Ph, COOEt), and some tetra- and hexahydro derivatives were determined by the classical shake-flask technique at ambient temperature (81MI4 82MI9). Hansch-type 7r values of the substituent (R-R2) were also calculated. The apparent octanol-water partition coefficients of seg-anserine 6 and its 7-methyl derivative were measured (88MI14). The pAa values and apparent octanol-water partition coefficients (at pH 7.4) of risperidone 7 (92MI20, 92MI30), its 9-hydroxy derivative (92MI30), and ocaperidone 8 were reported (92MI20). 

Scordo MG, Spina E, Facciola G, Avenoso A, Johansson I, Dahl M-L. Cytochrome P450 2D6 genotype and steady state plasma levels of risperidone and 9-hydroxy risperidone. Psychopharmacology 1999 147 300-305. 

A 21-year-old woman with a 2-year history of bipolar disorder stopped all of her medication when she discovered that she was pregnant she was given risperidone 2.5 months after childbirth, gradually increasing to a steady-state dosage of 6 mg/day. Risperidone and 9-hydroxyrisperidone concentrations in plasma and breast milk were measured, and calculations indicated that a suckling infant would receive only 0.84% of the maternal dose as risperidone and 3.46% as 9-hydroxy-risperidone. 

Plasma concentrations of risperidone and 9-hydroxy-risperidone were measured in 44 patients (aged 26-63 years) treated with risperidone alone (n = 23) or comedicated with carbamazepine (n = 11) (154). 

Risperidone is an antipsychotic agent. The compound is metabolized into two major metabolites, of which the 9-hydroxy analogue is biologically active and the 7-hydroxy analogue is not. Bioanalytical methods for risperidone should have a sub-ng/ml LOQ, discriminate between the 7- and 9-hydroxy metabolites, and should be selective towards other psychotropic drugs, which may be used simultaneously by patients. 

The simultaneous determination of risperidone and its 9-hydroxy metabolite by LC-MS was reported [44]. The analytes were extracted from plasma (adjusted to pH 10.5) by LLE with 15% dichloromethane in pentane. LC separation was achieved on a 50x4.6-mm-ID phenyl-hexyl column (5 gm) using an isocratic mobile phase consisting of 50% acetonitrile, 45% methanol, and 5% 0.15 mmol/1 aqueous ammonium acetate (AmOAc). Positive-ion ESI-MS was applied in SRM mode. Good linearity was obtained between 0.1 and 100 ng/ml. The LQQ was 0.1 ng/ml. The method was applied to study pharmacokinetic parameters and for therapeutic drag monitoring in patients. 

Figure 11.3 Chromatograms of risperidone (left panels) and monohydroxy-risperidone (right panels), (a) plasma spiked at 0.1 ng/ml with risperidone and 9-hydroxy risperidone, and (b) plasma from a volrmteer 3 h after oral administration of 2 mg risperidone, showing the separation between the 7-hydroxy and 9-hydroxy metabolite. Reprinted from [14] with permission. 2003, Elsevier Science BV.

From the selected applications in Ch. 11.4, it can be concluded that LLE is frequently applied, e.g., in the extraction of risperidone and its 9-hydroxy metabolite [44], of cholesterol-reducing dmgs [51-53], MPH [58], and of LOR and DCL [63, 66, 68]. Next to an one-step LLE followed by evaporation to dryness of the organic layer, two-step LLE procedures with back-extraction to an aqueous phase have been reported as well, e.g., for reserpine [42], atorvastatin [50], and LOR [63]. 

An addition (1994) to the antipsychotic armory is risperidone (Risperdal). Although still a member of the second generation, it may well be a member of its elite because of its alleged ties to both DA, D2 and serotonin type 2 receptors. Histamine and a receptors may also have connections to this agent. The extent of affinities of the latter three, however, are not known. The 9-hydroxy metabolite of risperidone is equally effective. 

The active metabolite hydroxy-risperidone has a half-life of 24 h. 

A pilot study in 6 psychiatric patients taking risperidone 1 to 3 mg twice a day for 1 to 4 weeks followed by 2 to 4 weeks of combined treatment with mirtazapine 15 to 30 mg at night, found that mirtazapine did not affect the plasma levels of risperidone or its 9-hydroxy metabolite. Data from another patient suggest that giving risperidone with mirtazapine does not result in clinically relevant changes in the plasma levels of mirtazapine. Concurrent use did not appear to increase the incidence of adverse effects, but the number of patients was limited. ... 

Risperidone and its 9-hydroxy metabolite were isolated from plasma and separated on base deactivated Cjg column (2 = 278nm). A 70/30 water (0.1 M KH2PO4 to pH 2.2 with H3P04)/acetonitrile mobile phase generated baseline separation and elution in undra Smin. A calibration range of 5-100ng/mL was reported with detection limits of 1 ng/mL. The retention times for six potential antidepressant drug interferents were tabulated [1514]. 

Haloperidol (Haldol), risperidone (Risperdal), loxapine (Loxitane), ziprasidone (Geodon), quetiapine (Seroquel), clozapine (Clozaril), aripiprazole (Abilify), and thioridazine (Mellaril) are targeted in this solid phase extraction (SPE), liquid chromatography— tandem mass spectrometry (LC-MS/MS) method. Both 9-hydroxy-risperidone (Paliperiodone), an equipotent metabolite, and mesoridazine (Serentil) are also included in this method as they are pharmacologically active major metabolites of risperidone and thioridazine, respectively (4). Olanzapine (Zyprexa) can be quantified with this instrument method however, the extraction method is a liquid-liquid basic extraction (see Note 1). Due to the subsequent administration of antidepressants in conjunction with antipsychot-ics, this method can also be used for many of the common antidepressants, including the selective serotonin reuptake inhibitors (SSRIs) (see Note 2). 

Cardiovascular QT prolongation associated with risperidone is predominantly related to its 9-hydroxy metabolite paliperidone. A study of 61 patients on risperidone foxmd significant positive correlation between plasma paliperi-done levels and a significant positive correlation between age- and dose-corrected plasma paliperidone levels [247 ]. 

Suzuki Y, Fukui N, Watanabe J, Ono S, Sugai T, Tsuneyama N, et al. QT prolongation of the antipsychotic risperidone is predominantly related to its 9-hydroxy metabolite paliperidone. Hum Psychopharmacol 2012 27(l) 39-42. 

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