Automated analysis of quetiapine and other antipsychotic drugs in human blood by high performance-liquid chromatography with column-switching and spectrophotometric detection.

An automated HPLC method with column switching is described for the determination of quetiapine, clozapine, perazine, olanzapine and metabolites in blood serum. After clean-up on silica C8 material (20 microm particle size) drugs were separated on ODS Hypersil C18 material (5 microm; column size 250 mm x 4.6 mm i.d.) within 25 min and quantified by ultraviolet (UV) detection at 254 nm. The limit of quantification ranged between 10 and 50 ng/ml. At therapeutic concentrations of the drugs, the inter-assay reproducibility was below 10%. Analyses of drug concentrations in serum of 75-295 patients treated with therapeutic doses of the antipsychotic drugs revealed mean+/-S.D. steady state concentrations of 139+/-136 ng/ml for quetiapine, 328+/-195 ng/ml for clozapine, 48+/-27 ng/ml for olanzapine and 71+/-52 ng/ml for perazine. The method was thus suitable for routine therapeutic drug monitoring and may be extended to other drugs.

Different effects of amitriptyline and imipramine on the pharmacokinetics and metabolism of perazine in rats.

The aim of this study was to search for possible effects of imipramine and amitriptyline on the pharmacokinetics and metabolism of perazine at steady state in rats. Perazine (10 mg kg(-1), i.p.) was administered to rats twice daily for two weeks, alone or jointly with imipramine or amitriptyline (10 mg kg(-1) i.p.). Concentrations of perazine and its two main metabolites (5-sulphoxide and N-desmethylperazine) in the plasma and brain were measured at 30 min (Cmax), 6h and 12h (slow disposition phase) after the last dose of the drugs. Liver microsomes were prepared 24 h after withdrawal of the drugs. Amitriptyline increased the plasma and brain concentrations of perazine (up to 300% of the control) and N-desmethylperazine, while not affecting those of 5-sulphoxide. Imipramine only tended to increase the neuroleptic concentration in the plasma and brain. Studies with control liver microsomes showed that amitriptyline and imipramine added to the incubation mixture in-vitro, competitively inhibited N-demethylation (Ki (inhibition constant) = 16 microM and 164 microM, respectively) and 5-sulphoxidation (Ki = 57 microM and 86 microM, respectively) of perazine, amitriptyline being a more potent inhibitor of perazine metabolism, especially with respect to N-demethylation. Studies with microsomes of rats treated chronically with perazine or tricyclic antidepressants, or both, did not show significant differences in the rate of perazine metabolism between perazine- and perazine+antidepressant-treated rats. The data obtained were compared with the results of analogous experiments with promazine and thioridazine. It was concluded that elevations of perazine concentration were caused by direct inhibition of the neuroleptic metabolism by the antidepressants. Similar interactions, possibly leading to exacerbation of the pharmacological action of perazine, may be expected in man. Since the interactions between phenothiazines and tricyclic antidepressants may proceed in two directions, reduced doses of both the neuroleptic and the antidepressant are recommended when the drugs are administered jointly.

Pharmacokinetics of phenothiazine neuroleptics after chronic coadministration of carbamazepine.

The aim of the present study was to assess the influence of carbamazepine on the pharmacokinetics of the two phenothiazine neuroleptics thioridazine and perazine in rats. The obtained results are compared with the results of analogical experiments concerning promazine. Thioridazine or perazine (10 mg/kg i.p.) were administered twice a day for two weeks alone or jointly with carbamazepine (15 mg/kg i.p. during the 1st week, and 20 mg/kg i.p. during the 2nd week of treatment). Concentrations of the neuroleptics and their main metabolites in the plasma and brain were measured at 30 min, 6 and 12 h after the last dose of the drugs. Carbamazepine decreased the concentrations of thioridazine and its metabolites (especially mesoridazine and sulforidazine) in plasma at 30 min and 6 h after the last dose of the drugs. Similar changes in the concentrations of thioridazine and its metabolites were observed at 6 h in the brain. Carbamazepine did not significantly influence the pharmacokinetics of perazine. In vitro studies with liver microsomes of control rats revealed that carbamazepine added to the incubation mixture inhibited N-demethylation of thioridazine via mixed mechanism, but it did not influence significantly 2- or 5-sulfoxidation of the neuroleptic. In the case of perazine, no distinct inhibition of its N-demethylation or sulfoxidation by carbamazepine was observed. Neither carbamazepine nor the neuroleptics, administered separately or jointly for two weeks, significantly influenced the concentrations of cytochromes P-450 and b-5 in the liver. Carbamazepine++ given chronically decreased the rate of N-demethylation and had a tendency to accelerate 2-sulfoxidation of thioridazine, both when given alone (as compared to the control) and when coadministered with thioridazine (as compared to the thioridazine-treated group). In contrast, chronic treatment with carbamazepine alone, significantly increased the rate of perazine N-demethylation. When carbamazepine was coadministered with perazine, the effect was less pronounced. In conclusion, carbamazepine given jointly with thioridazine or promazine at pharmacological doses to rats accelerates the metabolism of the neuroleptics, which is not the case with perazine. The observed induction proceeds by metabolic pathways other than N-demethylation or sulfoxidation. The different effect of carbamazepine on the N-demethylation of thioridazine and perazine in liver microsomes of control and carbamazepine-treated rats implicates that the two reactions are not catalyzed by the same enzyme. Such an induction of neuroleptic metabolism by carbamazepine in patients may worsen psychotic symptoms.

Residual symptoms and P300 in schizophrenic outpatients.

A reduced P300 amplitude has often been found to be related to schizophrenic psychopathology. It is still unclear, however, whether this relationship is trait- or state-dependent. We investigated 88 stabilized schizophrenic outpatients during a 2-year follow-up period. Multivariate analyses revealed that patients who had reduced P300 amplitudes showed pronounced residual symptoms, especially thought disorder (Brief Psychiatric Rating Scale). Intraindividual changes in that psychopathology were not correlated to corresponding changes of the P300 amplitude, so the relationship between schizophrenic psychopathology and P300 amplitude appears to be, at least in part, trait-dependent. A reduced P300 amplitude may characterize a subgroup of schizophrenic patients with a disposition to cognitive disturbances and incomplete remissions.

Early serum levels of neuroleptics do not predict therapeutic response in schizophrenia.

Thirty-six acute schizophrenics were included in a 28-day open treatment study with the neuroleptic perazine. Peak serum levels of parent drug and its main inactive metabolite desmethyl-perazine were assessed 2 hours after an oral test dose given at the beginning of the study. Whereas peak levels of perazine were not significantly different in treatment responders and nonresponders, desmethyl-perazine was significantly higher in nonresponders. The ratio between desmethyl-perazine and perazine was not predictive of (non-) response to neuroleptic treatment in schizophrenia.

Monitoring of serum bioactivity levels of perazine and its metabolites by radioreceptor assay.

The bioactivity of perazine and its metabolites in human serum was analysed by radioreceptor assay. The IC50 value (the concentration eliciting a 50% blockade of 3H-spiroperidol binding to the dopamine receptor in a membrane suspension of porcine striatum) was for perazine 175 nmol/l, and for its metabolites perazine sulfoxide 1050 nmol/l, desmethylperazine 330 nmol/l, N-(3-phenothiazin-10-yl-propyl)-ethylenediamine 2800 nmol/l, and N-(3-phenothiazin-10-yl-propyl)-N'-methylethylenediamin 2850 nmol/l. Thus, perazine metabolites possess low affinity to the dopamine receptor. In a pilot study we measured the bioactivity of perazine and its metabolites in sera of perazine-treated psychiatric patients by radioreceptor assay and compared the results to levels obtained by high-performance thin-layer chromatography; the correlation coefficient r was 0.85 and the slope 0.95 (n = 11). Thus serum perazine can be adequately monitored by radioreceptor assay, as evidenced by the results from high-performance thin-layer chromatography.

Prediction and evaluation criteria in perazine therapy of acute schizophrenics. Pharmacokinetic data.

Twenty-eight patients with acute schizophrenic illness received an oral daily dose of 200-800 mg perazine (Taxilan) for 4 weeks. Weekly plasma level determinations showed a constant perazine concentration from day 7 to day 28, whereas the equilibrium level of its metabolite desmethyl perazine was only achieved at day 14; on an average it amounted to twice the level of perazine. Additional measurements were carried out 2 and 4 h after administration of the morning dose on day 14. The maximal increase of the perazine concentration was usually reached after 2 h; though it varied between 7 and 240% of the morning level, a close correlation existed between minimal and maximal levels. The perazine fraction not bound to plasma proteins was found to be 3.1-5.5% on day 21. The percent improvement in target syndromes during 4 weeks of neuroleptic therapy, as documented with the AMDP system, was most marked in those patients who had perazine levels in the 100-230 ng/ml range at day 28; patients with lower or higher levels improved significantly less. Curvilinear relationships also appeared to exist between improvement and free perazine concentration as well as maximal level on day 14. With regard to total scores on the Brief Psychiatric Rating Scale or scores of higher-order factors, no significant relationship between improvement and perazine level was found. The desmethyl perazine concentration did not exhibit a significant relationship to the therapeutic result. The pharmacokinetic parameters investigated seem to have a limited influence on the clinical outcome.(ABSTRACT TRUNCATED AT 250 WORDS)

The binding of chemically different psychotropic drugs to alpha 1-acid glycoprotein.

The clinical significance of the high-affinity binding of psychotropic compounds to alpha 1-acid glycoprotein (alpha 1-AGP) in human serum has not been established yet. However, this binding may be of considerable theoretical interest since glycoproteins play a prominent role in the structure of cell membranes. In order to elucidate the nature of the binding to alpha 1-AGP several typical psychotropic compounds (diazepam, haloperidol, imipramine, perazine, phenobarbital and phenytoin) were investigated by means of equilibrium dialysis. The results suggest that among the classical CNS-drugs only those with a tricyclic structure are bound to two binding sites. Possible reason for the widely differing binding of a series of drugs are discussed in terms of their different chemical structure.

Plasma protein binding of perazine and amitriptyline in psychiatric patients.

The free fraction of amitriptyline (AT), measured by equilibrium dialysis in plasma from 29 AT-treated depressed patients, was 5.4-9.8% (mean 7.7%), which was the same as the values in 26 healthy controls (4.9-9.6%, mean 7.6%). The plasma levels of lipoproteins, as reflected by total cholesterol, and of alpha 1-acid glycoprotein (alpha 1-AGP) did not differ between the two groups. the free fraction of AT in both exhibited a significant negative correlation with the concentrations of those two proteins. The unbound fraction of perazine (PER) was the same (3.1-5.9%, mean 4.4%) in plasma from 22 schizophrenic patients and from 24 healthy volunteers (2.9-6.0%, mean 4.5%). However, in patient plasma alpha 1-AGP was significantly higher (mean 1.07 vs 0.81 mg/ml) and total cholesterol tended to be lower (mean 173 vs 201 mg/100 ml) than in plasma from normals. In consequence, the free fraction of PER was negatively correlated with the alpha 1-AGP concentration in plasma from patients and with the cholesterol level in plasma from control subjects; the other correlations were not significant. In 7 patients, the alpha 1-AGP level was normal prior to Per treatment. Serial blood samples from 6 patients revealed a consistent elevation of alpha 1-AGP above its pretreatment level during 4 weeks of PER administration in 5 of the subjects and a transient increase in one other. while low lipoprotein levels in schizophrenics seem to be a disease-related trait, the increase of alpha 1-AGP may be a drug effect.

Outcome and risks of ultra-long-term treatment with an oral neuroleptic drug. Relationship between perazine serum levels and clinical variables in schizophrenic outpatients.

In 33 schizophrenic patients treated continuously as outpatients with perazine over two decades, the rehospitalization rate decreased from 0.58 before treatment to 0.07 during treatment. The intensity of psychopathologic symptoms and the side effects were found to be remarkably low. The high intraindividual constancy of perazine plasma levels and the tight correlation between dose and plasma levels indicated satisfactory patient compliance. Plasma levels amounted to only 25% of those under acute treatment and correlated positively with the severity of the disease. Higher plasma levels coincided with more frequent side effects such as slightly pathologic liver function and moderate impairment of oral glucose tolerance. The results suggest that low-dose maintenance treatment of schizophrenic patients with oral neuroleptics is effective and relatively safe.

[Metabolism and excretion of the neuroleptic drug perazine in healthy volunteers]. / Stoffwechsel und Ausscheidung des Neuroleptikums Perazin bei gesunden Versuchspersonen.

The renal and faecal excretion of a single dose of 75 mg 35S-labelled perazine was investigated. The time course of the total radioactivity in plasma could not be adjusted satisfactorily to a Bateman function, whereas the renal excretion of radioactivity corresponded to an open two-compartment model. The marked interindividual variation of the metabolic profile, and of plasma half-lives reported in patients was not observed in normal volunteers. Thus, it is suggested that such interindividual variance is related to the special conditions in psychiatric patients such as individual pretreatment strategies.

Binding of perazine to alpha 1-acid glycoprotein.

The high-affinity binding of perazine to human serum-protein (non-albumin binding) was previously investigated by gel-chromatography. The immunoelectrophoretic identification of the binding agent as alpha 1-acid glycoprotein is described here. It was demonstrated by equilibrium dialysis that the average free fraction of 3H-perazine added to 22 sera from patients before neuroleptic treatment was 3.67 +/- 0.42%, and that there was a significant correlation between the alpha 1-acid glycoprotein content and the free fraction in these serum samples. This result is in accordance with what others have found for imipramine. It is suggested that the nature of this binding should be studied in more detail, since specific binding to alpha 1-acid glycoprotein may be related to the receptor binding of perazine and possibly other drugs.

Reliable routine method for determination of perazine in serum by thin-layer chromatography with an internal standard.

The use of a high-performance thin-layer chromatography linear chamber and of thioridazine as internal standard increases the performance of thin-layer chromatography (TLC) with direct densitometric scanning, and allows the rapid determination of serum levels of the neuroleptic drug perazine under usual therapeutic conditions. TLC is superior to gas-liquid chromatography in so far as the main metabolite desmethylperazine can be easily separated and detected by the same procedure.

The contribution of alpha 1-acid glycoprotein, lipoproteins, and albumin to the plasma binding of perazine, amitriptyline, and nortriptyline in healthy man.

Parameters for the binding of perazine (PER), amitriptyline (AT) and nortriptyline (NT) to plasma and to single plasma proteins were determined by equilibrium dialysis. The highest affinity (K at least 10(5) M-1) and lowest capacity (first site 1 mol/mol) towards all three drugs was exhibited by alpha 1-acid glycoprotein (alpha 1-AGP). From the parameters, alpha 1-AGP was estimated to contribute 43% to total binding of PER and 49 and 31%, respectively, to AT and NT binding in samples with normal protein concentrations. Fractions bound to total lipoproteins would amount to 32% (PER), 40 (AT) and 52% (NT), respectively, while the contribution of albumin would range from 11% (AT) to 25% (PER). The extent of the binding to plasma was compared with that to single proteins and their mixtures. Binding to combinations of alpha 1-AGP, lipoproteins and albumin exceeded that to plasma with PER but not with AT and NT. This leads to the assumption that additional plasma constituents interfere with PER binding.