Plasma Concentrations Of Risperidone Research Articles

Rifampin, a cytochrome P450 3A inducer, decreases plasma concentrations of antipsychotic risperidone in healthy volunteers

Although cytochrome P450 (CYP) 2D6 is often thought to be the only CYP responsible for the metabolism of risperidone, many reports suggest that CYP3A may be involved too. Rifampin, a potent CYP3A inducer, has been known to markedly decrease plasma concentrations of various drugs, which are concomitantly administered during treatment. To examine the effect of rifampin on plasma concentrations of a single oral dose of risperidone in healthy Thai male volunteers. In an open, randomized two-phase crossover study, separated by a 2-week period, 10 healthy Thai male volunteers received a single oral dose of 4-mg risperidone alone or with 600 mg rifampin, orally once daily for 5 days. Serial blood samples were collected at specific time points for a 48-h period. Risperidone was measured in plasma using high performance liquid chromatography with ultraviolet detection. Pharmacokinetic parameters were determined by using non-compartmental analysis. Co-administration with 600-mg rifampin once daily for 5 days was associated with a significant decrease in risperidone area under the curve (AUC(0-48)) and maximal concentration (C(max)) by 72% (157 x 49 +/- 48 x 80 vs. 42 x 66 +/- 7 x 81 ng/L/h; P<0 x 01) and 50% (32 x 44 +/- 6 x 05 vs. 16 x 16 +/- 2 x 73 ng/mL; P<0 x 05), respectively when compared with risperidone alone. Rifampin when used concurrently with risperidone significantly decreases the plasma concentration of risperidone. Our results provide in vivo evidence of the involvement of CYP3A in the metabolism of risperidone, in addition to CYP2D6. Thus, co-administration of risperidone with CYP3A inducer(s), including rifampin should be recognized or avoided in clinical practice.

Clinical Pharmacokinetics of Atypical Antipsychotics

In the past, the information about the dose-clinical effectiveness of typical antipsychotics was not complete and this led to the risk of extrapyramidal adverse effects. This, together with the intention of improving patients' quality of life and therapeutic compliance, resulted in the development of atypical or second-generation antipsychotics (SGAs). This review will concentrate on the pharmacokinetics and metabolism of clozapine, risperidone, olanzapine, quetiapine, amisulpride, ziprasidone, aripiprazole and sertindole, and will discuss the main aspects of their pharmacodynamics. In psychopharmacology, therapeutic drug monitoring studies have generally concentrated on controlling compliance and avoiding adverse effects by keeping long-term exposure to the minimal effective blood concentration. The rationale for using therapeutic drug monitoring in relation to SGAs is still a matter of debate, but there is growing evidence that it can improve efficacy, especially when patients do not respond to therapeutic doses or when they develop adverse effects. Here, we review the literature concerning the relationships between plasma concentrations of SGAs and clinical responses by dividing the studies on the basis of the length of their observation periods. Studies with clozapine evidenced a positive relationship between plasma concentrations and clinical response, with a threshold of 350-420 ng/mL associated with good clinical response. The usefulness of therapeutic drug monitoring is well established because high plasma concentrations of clozapine can increase the risk of epileptic seizures. Plasma clozapine concentrations seem to be influenced by many factors such as altered cytochrome P450 1A4 activity, age, sex and smoking. The pharmacological effects of risperidone depend on the sum of the plasma concentrations of risperidone and its 9-hydroxyrisperidone metabolite, so monitoring the plasma concentrations of the parent compound alone can lead to erroneous interpretations. Despite a large variability in plasma drug concentrations, the lack of studies using fixed dosages, and discrepancies in the results, it seems that monitoring the plasma concentrations of the active moiety may be useful. However, no therapeutic plasma concentration range for risperidone has yet been clearly established. A plasma threshold concentration for parkinsonian side effects has been found to be 74 ng/mL. Moreover, therapeutic drug monitoring may be particularly useful in the switch between the oral and the long-acting injectable form. The reviewed studies on olanzapine strongly indicate a relationship between clinical outcomes and plasma concentrations. Olanzapine therapeutic drug monitoring can be considered very useful in assessing therapeutic efficacy and controlling adverse events. A therapeutic range of 20-50 ng/mL has been found. There is little evidence in favour of the existence of a relationship between plasma quetiapine concentrations and clinical responses, and an optimal therapeutic range has not been identified. Positron emission tomography studies of receptor blockade indicated a discrepancy between the time course of receptor occupancy and plasma quetiapine concentrations. The value of quetiapine plasma concentration monitoring in clinical practice is still controversial. Preliminary data suggested that a therapeutic plasma amisulpride concentration of 367 ng/mL was associated with clinical improvement. A therapeutic range of 100-400 ng/mL is proposed from non-systematic clinical experience. There is no direct evidence concerning optimal plasma concentration ranges of ziprasidone, aripiprazole or sertindole.

Valproic Acid improves Psychotic Agitation without Influencing Plasma Risperidone Levels in Schizophrenic Patients

To investigate the effect of valproic acid on plasma levels of risperidone and its active metabolite, 9-hydroxyrisperidone under steady state conditions in 12 schizophrenic patients. The efficacy and tolerability for the combination treatment of valproic acid and risperidone were examined. The addition of valproic acid to risperidone significantly reduced total scores of PANSS positive symptoms, especially excitement and hostility scores, but did not change SAS scores. Addition of valproic acid did not alter plasma concentrations of risperidone or 9-hydroxyrisperidone or active moiety, and the risperidone/9-hydroxyrisperidone ratio. The combination of valproic acid with risperidone decreased plasma levels of HVA, but not those of MHPG; additionally, treatment with this combination was found to reduce dopaminergic activity. These results suggest that the addition of valproic acid to risperidone is both effective and well tolerated for treating excitement and impulsiveness in schizophrenic patients without influencing the metabolism of risperidone, and treatment with valproic acid and risperidone.

Risperidone plasma concentrations after treatment with risperidone oral solution and fine granules

Risperidone plasma concentrations after treatment with risperidone oral solution and fine granules

Multiple dose pharmacokinetics of risperidone and 9-hydroxyrisperidone in Chinese female patients with schizophrenia

To study the multiple dose clinical pharmacokinetics of risperidone and its main active metabolite, 9-hydroxyrisperidone, in Chinese female patients with schizophrenia. The subjects were 23 Chinese female inpatients aged 18-65 years who met the CCMD-III (third revision of the Chinese Criteria of Mental Disorders) criteria for schizophrenia. Subjects were tested after 17 d of treatment with 2 mg risperidone twice daily. Plasma concentrations of risperidone and 9-hydroxy-risperidone were assayed by using validated high performance liquid chromatography-mass spectrometry (HPLC-MS) methods. Risperidone was rapidly absorbed (Tmax was 1.6 h) and its T1/2 in plasma was short (3.2 h). 9-hydroxy-risperidone was quickly metabolized from the parent drug with a mean Tmax of 2.5 h. It had a long half-life of 24.7 h. The C(ss)(av) of risperidone and 9-hydroxy-risperidone were 36.9+/-33.1 and 110.6+/-30.5 microg x h x L(-1), respectively, and the AUC(ss)0-12 were 443.2+/- 397.4 and 1327.2+/- 402.3 microg x h x L(-1), respectively. CL/F and V/F of risperidone were 8.7+/- 6.2 L/h and 34.1+/- 24.3 L, respectively. Interindividual variations for pharmacokinetic parameters were quite large for risperidone. All 23 subjects experienced high prolactin levels when treated with risperidone. However there was no correlation between prolactin level and the concentration of risperidone, 9-hydroxy-risperidone, or the active moiety. Risperidone showed large interindividual variations in pharmacokinetics. Administration of risperidone resulted in high serum prolactin levels. The results indicate that systemic exposure to risperidone and 9-hydroxy-risperidone in female Chinese schizophrenic patients is higher relative to published data for white Caucasian patients. Larger studies regarding the PK/PD relationship may be required to develop a reasonable clinical dosage regimen for Chinese female patients.

A PET Study Evaluating Dopamine D2 Receptor Occupancy for Long-Acting Injectable Risperidone

Long-acting injectable risperidone represents the first clinically available depot atypical antipsychotic. The present study used positron emission tomography (PET) to evaluate its dopamine D(2) binding profile at doses of 25, 50, or 75 mg administered every 2 weeks. After achieving stabilization with one of the doses, nine patients with a diagnosis of schizophrenia or schizoaffective disorder underwent [(11)C]raclopride PET to measure D(2) occupancy. Participants were scanned twice during the 2-week injection interval: within 3 days after injection (postinjection) and within 5 days before the next injection (preinjection). At the same time, plasma was collected for measurements of risperidone plus 9-hydroxyrisperidone. Mean post- and preinjection D(2) occupancy levels for the 25-, 50-, and 75-mg doses were 71.0% and 54.0%, 74.4% and 65.4%, and 81.5% and 75.0%, respectively. There was a significant correlation between dose and plasma concentrations of risperidone plus 9-hydroxyrisperidone, and the estimated plasma concentration associated with 50% D(2) occupancy (ED(50)) was 11.06 ng/ml. Prolactin levels were not correlated with drug levels or D(2) occupancy. All three doses of injectable risperidone showed peak D(2) occupancy levels above the 65% threshold associated with optimal clinical response; the 75-mg dose approximated the 80% threshold linked to increased risk of extrapyramidal symptoms. Doses of 25 or 50 mg should provide therapeutic efficacy while minimizing the risk of extrapyramidal symptoms.

Dose-Dependent Interaction of Paroxetine With Risperidone in Schizophrenic Patients

Augmentation with paroxetine (10-40 mg/d) for antipsychotic treatment may improve the negative symptoms in schizophrenic patients but involves a risk of drug-drug interaction. We studied the effects of paroxetine on plasma concentrations of risperidone and 9-hydroxyrisperidone and their clinical symptoms in risperidone-treated patients. Twelve schizophrenic inpatients with prevailingly negative symptoms receiving risperidone 4 mg/d were, in addition, treated with incremental doses of paroxetine for 12 weeks (10, 20, and 40 mg/d for 4 weeks each). 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. Risperidone concentrations during coadministration of paroxetine 10, 20, and 40 mg/d were 3.8-fold (95% confidence interval, 3.2-5.8, P < 0.01), 7.1-fold (95% confidence interval, 5.3-16.5, P < 0.01), and 9.7-fold (95% confidence interval, 7.8-22.5, P < 0.01) higher than that before paroxetine coadministration, respectively. Active moiety (risperidone plus 9-hydroxyrisperidone) concentration was not increased during the paroxetine 10 mg/d (1.3-fold, not significant) or 20 mg/d (1.6-fold, not significant), but were significantly increased by 1.8-fold (95% confidence interval, 1.4-2.7, P < 0.05) during the paroxetine 40 mg/d. Significant improvement in negative symptoms was observed from 10 to 40 mg/d of paroxetine, whereas scores in extrapyramidal side effects during 20 and 40 mg/d of paroxetine were significantly higher than baseline score. This study indicates that paroxetine increases plasma risperidone concentration and active moiety concentration in a dose-dependent manner. Low-dose coadministration of paroxetine with risperidone may be safe and effective in the treatment of schizophrenic patients with negative symptoms.

Cytochrome P450 3A inhibitor itraconazole affects plasma concentrations of risperidone and 9-hydroxyrisperidone in schizophrenic patients

Despite the belief that cytochrome P450 (CYP) 2D6 alone is responsible for the metabolism of risperidone, several studies suggest that CYP3A may be involved. The aim of this study was to evaluate the effect of itraconazole, a CYP3A inhibitor, on the plasma concentrations of risperidone and 9-hydroxyrisperidone in schizophrenic patients in relation to CYP2D6 genotype. Nineteen schizophrenic patients treated with 2 to 8 mg/d of risperidone received 200 mg/d of itraconazole for a week. Plasma concentrations of risperidone and 9-hydroxyrisperidone were measured immediately before and after itraconazole treatment, as well as at 1 week after itraconazole treatment was stopped, together with clinical assessment by use of the Udvalg for Kliniske Undersøgelser Side Effect Rating Scale and the Brief Psychiatric Rating Scale. Dose-normalized plasma concentrations of risperidone and 9-hydroxyrisperidone before itraconazole treatment (0.9 +/- 0.8 ng.mL(-1).mg(-1) and 6.9 +/- 3.3 ng.mL(-1).mg(-1), respectively) were significantly elevated after itraconazole treatment (1.6 +/- 1.3 ng.mL(-1).mg(-1) and 11.3 +/- 4.5 ng.mL(-1).mg(-1)) and decreased 1 week after its discontinuation (1.0 +/- 0.8 ng.mL(-1).mg(-1) and 7.2 +/- 3.7 ng.mL(-1).mg(-1)) (P < .01). 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). Itraconazole increased the concentrations of risperidone by 69% (P < .001) and 75% (P < .01) in CYP2D6 extensive and poor metabolizers, respectively. In addition, the active moiety (risperidone plus 9-hydroxyrisperidone) also increased similarly, by 71% (P < .001) and 73% (P < .05), respectively, with itraconazole, without a significant difference between CYP2D6 genotypes. The scores on the Brief Psychiatric Rating Scale decreased significantly but only by 6% after itraconazole treatment (P < .05); however, the scores on the Udvalg for Kliniske Undersøgelser Side Effect Rating Scale were not changed. Our results provide in vivo evidence of the involvement of CYP3A in the disposition of risperidone and 9-hydroxyrisperidone. In addition to CYP2D6, treatment with CYP3A inhibitor(s) including itraconazole may influence clinical symptoms and risperidone side effects.

Effect of fluvoxamine on plasma risperidone concentrations in patients with schizophrenia

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. Additional fluvoxamine, at the dose of 100 mg/day, was administered for 4 weeks to patients stabilized on risperidone (3–6 mg/day). Mean plasma concentrations of risperidone, 9-OH-risperidone and the active moiety (sum of the concentrations of risperidone and 9-OH-risperidone) were not significantly modified following co-administration with fluvoxamine. After 4 weeks, fluvoxamine dosage was increased to 200 mg/day in five patients and then maintained until the end of week 8. At final evaluation, mean plasma levels of risperidone active moiety were not modified in the six patients who were still receiving the initial fluvoxamine dose, while concentrations increased slightly but significantly (by a mean 26% over pretreatment; P < 0.05) in the subgroup of five subjects treated with a final dose of 200 mg/day. Fluvoxamine co-administration with risperidone was well tolerated and no patient developed extrapyramidal side effects. These findings indicate that fluvoxamine at dosages up to 100 mg/day is not associated with clinically significant changes in plasma risperidone concentrations. However, higher doses of fluvoxamine may elevate plasma risperidone levels, presumably as a result of a dose-dependent inhibitory effect of fluvoxamine on CYP2D6-and/or CYP3A4-mediated 9-hydroxylation of risperidone.

D2 dopamine receptor occupancy, risperidone plasma level and extrapyramidal motor symptoms in previously drug-free schizophrenic patients

A relationship between high D2 occupancy (above 80%) and extrapyramidal-motor symptoms under neuroleptic treatment has been observed in several neuroimaging studies. We investigated the striatal dopamine D2 receptor occupancy, risperidone plasma level and extrapyramidal-motor symptoms in drug-free schizophrenic patients. Ten schizophrenic patients were treated with 3 - 6 mg risperidone daily. After four weeks administration, a [(123)I]iodobenzamide ([(123)I]IBZM)-single photon emission tomography (SPET) scan for determination of D2 receptor occupancy was carried out (in eight responders) and compared to a control group. Plasma concentrations of risperidone and its active metabolite 9-hydroxyrisperidone (active moiety) were determined by high performance liquid chromatography and electrochemical detection. Extrapyramidal-motor symptoms were assessed by means of the Simpson-Angus-Scale and a handwriting test before treatment and coincident with the scan. The D2 receptor occupancy (Mean 62%, SD 13%) positively correlated with the plasma level of the risperidone active moiety as well as with the reduction in handwriting area. Multiple linear regression revealed an inherent relationship with a coefficient of determination of r = 0.956 (p = 0.02). No clinical relevant extrapyramidal-motor symptoms were observed. In drug-free schizophrenic responders, the simultaneous assessment of both plasma level and reduction in handwriting area may be a useful clinical tool for a surrogate estimate of D2 receptor occupancy under risperidone treatment. This may help to minimize or even prevent extrapyramidal-motor symptoms.

Influence of age and gender on risperidone plasma concentrations

There is limited information on gender- and age-specific effects on plasma concentrations of risperidone and its active metabolite, 9-hydroxyrisperidone. The present study investigated dose- and weight-adjusted plasma concentrations of risperidone and its metabolite in three age groups (45 years, 45-60 years, over 60 years). Gender-specific differences were examined in the whole sample and for the premenopausal subgroup. One hundred and twenty-nine patients (18-93 years) were included in the study, 52 (40%) male and 77 (60%) female. Concentrations of risperidone and 9-hydroxyrisperidone were measured at steady-state by high-performance liquid chromatography with electrochemical detection (HPLC-ED). When total plasma concentrations (risperidone plus 9-hydroxyrisperidone) were adjusted for daily maintenance dose (ng/mL/mg C/D ratio), significant differences between all age groups were found. We found a mean increase of the C/D ratio by 34.8% per decade in patients older than 42 years. No significant sex-related differences in the average plasma concentrations were observed for the whole sample and for the premenopausal subgroup. This study shows clear evidence of higher risperidone total plasma concentrations for patients over 40 years of age. This linear increase (over 30% per decade) may then lead to an increased incidence of adverse effects in elderly patients.

Effect of verapamil on pharmacokinetics and pharmacodynamics of risperidone: In vivo evidence of involvement of P-glycoprotein in risperidone disposition

A recent in vitro study has shown that risperidone is a substrate of P-glycoprotein. The aim of this study was to confirm the effects of verapamil, a P-glycoprotein inhibitor, on the pharmacokinetics of risperidone. Two 6-day courses of either 240 mg verapamil daily, an inhibitor of P-glycoprotein, or placebo were administered in a randomized crossover fashion with at least a 4-week washout period. Twelve male volunteers took a single oral 1-mg dose of risperidone on day 6 of both courses. Plasma concentrations of risperidone, 9-hydroxyrisperidone, and prolactin were monitored up to 24 hours after dosing. Compared with placebo, verapamil treatment significantly increased the peak plasma concentration of risperidone by 1.8-fold and the area under the plasma concentration-time curve (AUC) from 0 to 24 hours of risperidone by 2.0-fold but did not alter the elimination half-life. The AUC from 0 to 24 hours of 9-hydroxyrisperidone, but not other pharmacokinetic parameters, was significantly increased during verapamil treatment. However, the AUC from 0 to 4 hours and the AUC from 0 to 8 hours of prolactin concentrations were not increased by verapamil treatment despite the pharmacokinetic alterations. This study demonstrated that the bioavailability of risperidone was increased by verapamil, suggesting in vivo involvement of P-glycoprotein in the pharmacokinetics of risperidone.

Predominant Role of the 9-Hydroxy Metabolite of Risperidone in Elevating Blood Prolactin Levels

The atypical antipsychotic risperidone significantly raises plasma prolactin levels in patients, but clozapine, olanzapine, and quetiapine do not. The differences in neuroendocrine response may be connected with the metabolism of the medications. The authors examined the contributory role of risperidone's active metabolite 9-hydroxy-risperidone by measuring plasma concentrations of risperidone, 9-hydroxy-risperidone, and prolactin. Blood samples taken from 25 patients with psychotic disorders following 6 weeks of treatment with risperidone (mean dose=3 mg/day) were examined. Mean plasma concentrations of risperidone, 9-hydroxy-risperidone, and prolactin were 4.6, 19.4, and 49.3 ng/ml, respectively. The oral dose of risperidone correlated significantly with plasma concentrations of risperidone, 9-hydroxy-risperidone, active moiety, and prolactin. The plasma concentration of 9-hydroxy-risperidone, but not of risperidone, correlated significantly with increases in plasma prolactin. These data suggest that the 9-hydroxy metabolite plays a predominant role in risperidone's effect on prolactin release.

Plasma Concentrations of Risperidone and Olanzapine during Coadministration with Oxcarbazepine

Oxcarbazepine (OZC) is a second-generation antiepileptic drug (AED) that also may be used as a mood stabilizer. Unlike carbamazepine (CBZ), which is an inducer of the cytochrome P-450 isoforms and may accelerate the elimination of several therapeutic agents, OXC seems to have only a modest inducing action. The aim of this investigation was to evaluate the effect of a treatment with OXC on plasma concentrations of the new antipsychotics risperidone and olanzapine. OXC, at a dosage of 900-1,200 mg/day, was administered for 5 consecutive weeks to 25 outpatients, 10 men and 15 women, aged 25 to 64 years, with bipolar or schizoaffective disorder. Twelve patients were stabilized on risperidone therapy (2-6 mg/day) and 13 on olanzapine (5-20 mg/day). Steady-state plasma concentrations of risperidone and its active metabolite 9-hydroxyrisperidone (9-OH-risperidone) and olanzapine were measured by high-pressure liquid chromatography (HPLC) before addition of OXC and after 5 weeks from the start of adjunctive treatment. OXC caused only minimal and no significant changes in the mean plasma levels of risperidone (from 5.6 +/- 3.6 ng/ml at baseline to 4.8 +/- 2.6 ng/ml at week 5), 9-OH-risperidone (from 23.6 +/- 7.5 to 24.7 +/- 7.4 ng/ml), and olanzapine (from 26.5 +/- 5.7 ng/ml at baseline to 27.8 +/- 5.1 ng/ml). OXC coadministration with either risperidone or olanzapine was well tolerated. Our findings indicate that OXC does not affect the elimination of risperidone and olanzapine, thus confirming its weak inducing effect on hepatic drug-metabolizing enzymes.

Little Effects of Low Dosage of Levomepromazine on Plasma Risperidone Levels

In the present study, we investigated the effects of levomepromazine on plasma risperidone concentrations in a steady state. Twenty patients taking risperidone at a stable dose for more than 2 weeks who were considered to require levomepromazine coadministration were selected. The scores of excitement in BPRS significantly decreased 2 weeks after the coadministration of levomepromazine. Plasma risperidone concentrations and the ratio of risperidone and 9-hydroxyrisperidone (risperidone/9-hydroxyrisperidone) did not change between before and 2 weeks after the coadministration of levomepromazine. The extrapyramidal symptoms were not worsened by the coadministration of levomepromazine. These results suggest that a low dosage of levomepromazine, use as a sedative adjuvant to risperidone treatment, have no statistically significant effect on the trough plasma concentrations of risperidone.

Prediction of response to risperidone treatment with respect to plasma concencentrations of risperidone, catecholamine metabolites, and polymorphism of cytochrome P450 2D6

In the present study, we examined the relationships between plasma concentrations of risperidone and clinical responses, extrapyramidal symptoms, plasma levels of cotinine and caffeine, or cytochrome (cyp)2D6 genotypes. In addition, we also investigated the relationships between plasma levels of 3-methoxy-4-hydroxyphenylglycol (MHPG) or homovanillic (HVA) acid and clinical responses to risperidone. One hundred and 36 patients (male/female: 58/78, age 37+/-13 years) who met DSM-IV criteria for schizophrenia, schizoaffective disorder, delusional disorder and brief psychotic disorder, and who were being treated with risperidone alone, were evaluated regarding their clinical improvement and extrapyramidal symptoms using the Positive and Negative Syndrome Scale (PANSS) and Simpson and Angus (SAS), respectively, and plasma levels of cotinine, caffeine, MHPG and HVA were analysed by high-performance liquid chromatography. The cyp2D6*5 and *10 alleles were identified using the polymerase chain reaction. There was a positive correlation between plasma levels of risperidone plus 9-hydroxyrisperidone (active moiety) and SAS scores, but not the PANSS. Pretreatment HVA levels in responders were higher than those in nonresponders. In addition, there was a negative correlation between changes in HVA levels and improvement in PANSS scores. There was no association between plasma levels of risperidone and plasma levels of cotinine or caffeine. Furthermore, there were no differences in the risperidone/9-hydroxyrisperidone ratio, clinical improvements and extrapyramidal symptoms among cyp2D6 genotypes. These results indicate that pretreatment HVA levels and plasma concentrations of active moiety might play a part in predicting the clinical response and occurrence of extrapyramidal symptoms, respectively, when treating patients with risperidone.

The brain entry of risperidone and 9-hydroxyrisperidone is greatly limited by P-glycoprotein

P-glycoprotein (P-gp) in the brain capillary endothelial cell limits the entry of many drugs into the brain. Our previous in-vitro study using ATPase as a marker of P-gp activity suggested that risperidone might be effectively transported by P-gp. In the present study, we compared the concentrations of risperidone and its major pharmacologically active metabolite 9-hydroxyrisperidone (9-OH-risperidone), in plasma, brain and various other tissues between abcb1ab-/- knockout mice which are functionally devoid of P-gp in their blood-brain barrier vs. FVB wild-type mice. One hour after intraperitoneal injection of 4 microg/g risperidone, the brain concentrations and ratios of brain:plasma concentrations of risperidone (13.1-fold and 12-fold respectively, p<0.05) and 9-OH-risperidone (29.4-fold and 29-fold respectively, p<0.01) were significantly higher in the abcb1ab-/- mice than those in the FVB mice. These results indicate that P-gp in the blood-brain barrier significantly influences the brain concentrations of risperidone and 9-OH-risperidone by limiting their CNS access.

The role of cytochrome P450 enzymes in the metabolism of risperidone and its clinical relevance for drug interactions.

In the recent years it has been increasingly recognized that pharmacogenetical factors play an important role in the drug treatment. These factors may influence the appearance of side-effects and drug interactions due to interindividual differences in the activity of metabolizing enzymes. Risperidone in humans is mainly metabolized to 9-hydroxyrisperidone by the polymorphic cytochrome enzyme P450 2D6 (CYP2D6). Plasma concentrations of risperidone and 9-hydroxyrisperidone show large interindividual variability, which may be partly related to the activity of the CYP2D6 enzyme. Around seven percent of Caucasians have a genetically inherited impaired activity of the CYP2D6 enzyme. Debrisoquine metabolic ratio (a marker of CYP2D6 activity) and the number of CYP2D6 active genes have been related to risperidone plasma concentrations among patients during steady-state conditions. A large number drugs have been described to be metabolized by CYP2D6, and it is therefore important to evaluate the clinical significance of the impaired metabolism and possible drug interactions on the enzyme. Since risperidone/9-hydroxyrisperidone ratio strongly correlates with CYP2D6 enzyme activity and the number of CYP2D6 active genes, thus it might be a useful tool in clinical practice to estimate the possible risk of drug interactions due to impaired CYP2D6 enzyme activity. CYP3A4 is the most abundant drug metabolizing enzyme in humans, and in vitro and in vivo results suggest also a role for the enzyme in risperidone metabolism. The consideration of the implication of cytochrome P450 enzymes in risperidone metabolism may help to individualize dose schemes in order to avoid interactions and potentially dangerous side-effects, such us QTc interval lengthening among patients with cardiac risk factors.

Effects of various factors on steady-state plasma concentrations of risperidone and 9-hydroxyrisperidone: lack of impact of MDR-1 genotypes

Aims An in vitro study has suggested that risperidone is a substrate of P-glycoprotein, which is coded by MDR-1 gene. Thus, we studied the effects of major polymorphisms of the MDR-1 gene on plasma drug concentrations. Methods Subjects were 85 schizophrenic patients receiving 3 mg twice daily of risperidone. Sample collections were conducted 12 h after the bedtime dosing. Plasma concentrations of risperidone and 9-hydroxyrisperidone were quantified using LC/MS/MS. MDR-1 genotypes (C3435T and G2677T/A) and CYP2D6 genotypes were identified using PCR-RFLP methods. Results There was no difference in geometric mean (95% CI) of steady-state plasma concentration of risperidone between C3435T genotypes [C/C, C/T, T/T; 2.06 (1.63, 6.47), 2.96 (3.10, 7.91), 2.28 (1.81, 8.04) ng ml−1, P = 0.759] or G2677T/A genotypes [G/G, G/T or A, T or A/T or A; 1.62 (0.08, 6.07), 2.64 (3.25, 7.10), 2.71 (2.77, 8.72) ng ml−1, P = 0.625] or 9-hydroxyrisperidone between C3435T genotypes [38.3 (33.7, 50.1), 34.9 (32.9, 42.0), 35.7 (31.7, 42.3) ng ml−1, P = 0.715] or G2677T/A genotypes [40.6 (33.0, 51.8), 35.0 (33.3, 42.4), 36.1 (32.8, 47.2) ng ml−1, P = 0.601]. Multiple regression analyses including CYP2D6 genotypes, sex, and age revealed that steady-state plasma concentration of risperidone correlated with the number of mutated alleles for CYP2D6 (standardized partial correlation coefficients (beta) = 0.540, P < 0.001) and those of 9-hydroxyrisperidone (standardized beta = 0.244, P = 0.038) and active moiety (standardized beta = 0.257, P = 0.027) correlated with age. 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.

Effects of various factors on steady-state plasma concentrations of risperidone and 9-hydroxyrisperidone: lack of impact of MDR-1 genotypes.

An in vitro study has suggested that risperidone is a substrate of P-glycoprotein, which is coded by MDR-1 gene. Thus, we studied the effects of major polymorphisms of the MDR-1 gene on plasma drug concentrations. Subjects were 85 schizophrenic patients receiving 3 mg twice daily of risperidone. Sample collections were conducted 12 h after the bedtime dosing. Plasma concentrations of risperidone and 9-hydroxyrisperidone were quantified using LC/MS/MS. MDR-1 genotypes (C3435T and G2677T/A) and CYP2D6 genotypes were identified using PCR-RFLP methods. There was no difference in geometric mean (95% CI) of steady-state plasma concentration of risperidone between C3435T genotypes [C/C, C/T, T/T; 2.06 (1.63, 6.47), 2.96 (3.10, 7.91), 2.28 (1.81, 8.04) ng ml(-1), P = 0.759] or G2677T/A genotypes [G/G, G/T or A, T or A/T or A; 1.62 (0.08, 6.07), 2.64 (3.25, 7.10), 2.71 (2.77, 8.72) ng ml(-1), P = 0.625] or 9-hydroxyrisperidone between C3435T genotypes [38.3 (33.7, 50.1), 34.9 (32.9, 42.0), 35.7 (31.7, 42.3) ng ml(-1), P = 0.715] or G2677T/A genotypes [40.6 (33.0, 51.8), 35.0 (33.3, 42.4), 36.1 (32.8, 47.2) ng ml(-1), P = 0.601]. Multiple regression analyses including CYP2D6 genotypes, sex, and age revealed that steady-state plasma concentration of risperidone correlated with the number of mutated alleles for CYP2D6 (standardized partial correlation coefficients (beta) = 0.540, P < 0.001) and those of 9-hydroxyrisperidone (standardized beta = 0.244, P = 0.038) and active moiety (standardized beta = 0.257, P = 0.027) correlated with age. 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.