The Influence of the CYP3A4*22 Polymorphism and CYP2D6 Polymorphisms on Serum Concentrations of Aripiprazole, Haloperidol, Pimozide, and Risperidone in Psychiatric Patients.

INTRODUCTION: Cytochrome P450 3A4 (CYP3A4) is involved in the metabolism of greater than 50% of the prescribed drugs. Recently, the CYP3A4*22 allele was reported to be associated with lower CYP3A4 expression and activity. Quetiapine, an antipsychotic metabolized by only CYP3A4, displayed higher serum levels in CYP3A4*22 carriers. Aripiprazole, haloperidol, pimozide, and risperidone are antipsychotics that are metabolized by CYP3A4 and CYP2D6. We investigated to which degree the CYP3A4*22 single-nucleotide polymorphism affects serum concentrations of patients receiving these drugs and compared this with the influence of CYP2D6 polymorphisms. METHODS: Eight hundred thirty-four adult patients were included in this study, of whom 130 used aripiprazole, 312 used haloperidol, 86 used pimozide, and 396 used risperidone. Serum levels of the drug and, if available, their active metabolites were collected as well as information on dose. Patients were genotyped for CYP3A4*22 using restriction fragment length polymorphism analysis. Genotyping for CYP2D6 was done with allele-specific polymerase chain reaction. RESULTS: No differences were found in serum (dose-corrected) concentrations of the antipsychotics between CYP3A4*22 wild-type and carrier groups. In contrast, CYP2D6 genotype did affect dose-corrected concentrations of the antipsychotics: for example, median dose-corrected concentrations were 56%, 86%, and 400% higher in predicted poor metabolizers versus extensive metabolizers for aripiprazole (P = 0.004), haloperidol (P > 0.001), and risperidone (P < 0.001), respectively, although a multiple regression analysis showed that only 4% to 17% of the variation in these concentrations could be explained by CYP2D6 status. CONCLUSIONS: Heterozygous presence of CYP3A4*22 does not increase serum levels of antipsychotics metabolized by both CYP3A4 and CYP2D6, whereas CYP2D6 polymorphisms do affect serum levels to a limited extent.

Quantitative determination of pimozide in human plasma by liquid chromatography-mass spectrometry and its application in a bioequivalence study.

A simple, sensitive and specific LC-ESI/MS method was developed for the determination of pimozide in human plasma. Pimozide and cinnarizine (internal standard) were isolated from plasma samples by liquid-liquid extraction. The chromatographic separation was accomplished on a Thermo Hypersil-HyPURITY C18 reversed-phase column (150mmx2.1mm, i.d., 5microm) with the mobile phase consisting of 5mM ammonium acetate (pH 3.5, adjusted with acetic acid)-methanol-acetonitrile (39:5:56, v/v/v). The lower limit of quantification was 0.02ng/mL, and the assay exhibited a linear range of 0.025-12.800ng/mL. The established method has been successfully applied to a bioequivalence study of 2 pimozide formulations in 32 healthy male Chinese volunteers.

Practical application of guinea pig telemetry system for QT evaluation.

The purpose of this study was to evaluate a telemetry system for examining QT evaluation in the conscious free-moving guinea pig using 10 reference compounds whose effects on human QT interval are well established: 8 positive references (bepridil, terfenadine, cisapride, haloperidol, pimozide, quinidine, E-4031 and thioridazine), and 2 negative references (propranolol and nifedipine). Pharmacokinetic experiments were also performed for the 8 positive references. Telemetry transmitters were implanted subcutaneously in male Hartley guinea pigs, and the RR and QT intervals were measured. All 8 positive references prolonged QTc (QTc = k x QT/RR(1/2)) 10% or more during the 60 min observation period. When the values of the QTc changes were plotted against the serum concentrations, the resulting curves exhibited an anticlockwise hysteresis loop for all 8 references. In guinea pigs treated with haloperidol, changes of the T-wave shape from positive to flat were observed. The 2 negative references did not prolong the QTc. These findings suggest that the present telemetry guinea pig model is useful for QT evaluation in the early stages of drug development, because of the small body size of guinea pigs and their action potential configuration, which is similar to that of humans.

Sensitive assay for pimozide in human plasma using high-performance liquid chromatography with fluorescence detection: application to pharmacokinetic studies.

A method is described for the measurement of pimozide in human plasma using HPLC with fluorescence detection. The method is specific and sensitive in the range of concentrations seen in human plasma after conventional dosing (1-15 ng/ml) with a limit of quantification of 1 ng/ml. The calibration curves are linear for concentrations between 1 and 50 ng/ml. Within-day and inter-day coefficients of variation are less than 7.4% and 15.5%, respectively, at three concentrations of pimozide (2, 10 and 20 ng/ml). Intra-day and inter-day bias are less than 18.5% and 12.5%, respectively. A pharmacokinetic study conducted in a healthy volunteer administered 6 mg of pimozide orally demonstrates the utility of this method.

[Delusional disorders with delirium of somatic type]. / Trastorno delirante con delirio de tipo somático.

The delusional disturbance is characterized by the presence of persistent delusions that are not bizarre, which cannot be attributed to schizophrenia, mood state disorders, substance abuse or organic brain disease. We report a 37 years old male that presented the disease during the last seven years and had very little response to a two months course of pimozide, a neuroleptic whose effectiveness in this disease has been suggested.

The Scottish First Episode Schizophrenia Study. II. Treatment: pimozide versus flupenthixol. The Scottish Schizophrenia Research Group.

In a randomised double-blind study, 46 first episode schizophrenics were given pimozide or flupenthixol for up to 5 weeks; the mean daily dose at the end was 18.8 mg pimozide and 20 mg flupenthixol. There were no significant between-drug differences in the effect on mental state or behaviour; positive schizophrenic symptoms responded to treatment, negative symptoms did not. Most patients required anti-Parkinsonian medication. Poor response was associated with 'organicity'. A switch to maintenance therapy after 5 weeks, the outcome of successful treatment and patient cooperation, was achieved in only 54%. There was no relationship between plasma prolactin levels and severity of schizophrenic symptoms in unmedicated patients. Pimozide produced greater elevation of plasma prolactin. Plasma neuroleptic levels showed drug compliance was satisfactory throughout in only 54%.

Within-individual variation in steady state plasma levels of different neuroleptics and prolactin.

Eleven male chronic schizophrenics were given, serially, oral pimozide, fluphenazine, and flupenthixol; the two latter were also given intramuscularly as decanoates in oil. Oral haloperidol was given before and after each drug. Analysis of variance of steady state plasma levels of the different neuroleptics showed considerable within-individual variation in such levels, probably due to differences in absorption and metabolism and between routes of administration. The findings suggest that if a patient fails to respond to one neuroleptic, there may be good pharmacokinetic reasons for switching him to another belonging to a different group, or for giving the same neuroleptic by a different route of administration. The study also showed that previous administration of one neurololeptic may influence the steady state level of another. The various neuroleptics produced different effects on plasma prolactin levels.

Plasma prolactin and growth hormone levels in manic patients treated with pimozide.

During two weeks' treatment of 11 manic patients with pimozide there was close correspondence between the timecourse of improvement in clinical ratings and the rise in plasma prolactin between the second and fourteenth day. There were no significant differences in growth hormone levels during the manic episodes compared to recovery. These findings are discussed in relation to the role of dopamine in the release of prolactin and growth hormone, and in the pathogenesis of mania.

Pimozide versus Haloperidol in acute schizophrenia. A double blind controlled study.

Thirty acutely hospitalized schizophrenic patients were treated under double blind condition with either haloperidol (40-60 mg/day) or pimozide (40-60 mg/day) for 30 days. Ten patients in the pimozide and eleven in the haloperidol group showed a very good or good clinical response. There were no definite differences of treatment results as assessed by the Global Clinical Impression. Both groups showed a statistically significant decrease of the global scores of the Brief Psychiatric Rating Scale (p less than 0.01). There was a significant decrease of affective bluntedness and anergia in the pimozide but not in the haloperidol group. Extrapyramidal side effects were more pronounced in patients on pimozide who therefore needed more anticholinergic drugs. There was no consistent correlation between drug serum levels and global scores or single factors of the BPRS in either treatment group. It is concluded that pimozide in dose ranges from 40-60 mg has powerful antipsychotic properties indistinguishable from those of haloperidol but exerts stronger extrapyramidal side effects.

Intermittent pimozide versus fluphenazine decanoate as maintenance therapy in chronic schizophrenia.

In a double-blind trial, 34 male chronic schizophrenic day-patients or in-patients in a hostel ward continued on fluphenazine decanoate given mostly once fortnightly or were switched to pimozide, given on four days each week. Over nine months relapse rates were similar for both groups, and while fewer patients on pimozide were prescribed antiparkinsonian drugs one quarter developed buccolingual masticatory dyskinesia. Plasma pimozide levels suggested satisfactory drug compliance. Average plasma prolactin levels were within the normal rage for untreated men in one quarter of non-relapsing patients on pimozide and three quarters on fluphenazine.