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.

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.

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.

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.

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.

Determination of perazine serum levels by gas liquid chromatography under clinical routine conditions.

A quantitative gas liquid chromatographic method for the determination of serum levels of perazine (10-[3'-(1''-methyl-4''-piperazinyl)-propyl]-phenothiazine) is described. Perazine is used as a neuroleptic drug. The main problem consists in optimizing the chromatographic system. A sensitivity of appr. 60--150 nmol/1 (20--50 microgram/1) serum is achieved. Examples of optimization, analyses with patient samples, and the reproducibility of the results are presented.

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.

Gas-liquid chromotographic determination of perazine, thioridazine and thioridazine metabolites in human plasma.

A gas-liquid chromatographic method for the detection of perazine, thioridazine and its major metabolites in human plasma is presented. Repeated extraction, an internal standard and a temperature program with flame ionization detection make possible accurate and reproducible results with patients on therapeutic doses of these drugs. Examples of chromatograms after extraction of plasma are given.

[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.

[Specific binding of perazine, a piperazine side-chain phenothiazine drug, to a serum protein (author's transl)]. / Eine spezifische Serumproteinbindung des Neuroleptikums Perazin.

A binding of perazine to a serum protein of 48 000 D was determined by gel filtration. The affinity constant of the perazine-protein complex was found to be 5.42 X 10(6) mol/l corresponding to a specific binding of 70 ng/ml serum. This result may gather clinical relevance with regard to the "CNS-bioavailability" and individual response to perazine, the average therapeutic serum concentrations having been shown to range between appr. 50 and 200 ng/ml serum. A specific binding of perazine to human or bovine albumine could not be detected.

[Relationship between perazine serum concentration and clinical results in long-term treated schizophrenic outpatients (author's transl)]. / Beziehungen zwischen Serumkonzentration und klinischen Befunden bei langfristig mit Perazin behandelten schizophrenen Patienten.

The perazine serum concentration was determined with a new gaschromatographic method in 33 schizophrenic outpatients of our psychiatric catamnestic unit who had received perazine for a period of 18 years. A very high constancy of the perazine serum level could be demonstrated by repeated measurements. A close connection existed between perazine dosage and perazine serum level. Both findings suggest a very good complicance of these patients. Serum levels were correlated positively with the intensity of the psychopathologic symptoms as well as with the frequency of side-effects, particularly with slight changes of liver enzymes.

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.

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)

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.

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.

[Changes in drug elimination under the influence of perazine therapy (author's transl)]. / Anderung des Arzneimittelabbaus in der Leber unter der Behandlung mit Perazin

In 8 male patients who were treated with perazine for a schizophrenic psychosis (200-800 mg/die), the elimination rate of phenazone was investigated. Simultaneously determinations of plasma levels of perazine and desmethylperazine were carried out. The average half-life of phenazone was 27.0 h in perazine-treated patients and 11.2 h in controls. Correspondingly, the clearance of phenazone decreased from 47.0 ml/min to 18.9 ml/min under perazine, both differences being highly significant. The amount of 4-OH-phenazone, the principal hydroxylated metabolite excreted in the urine, was 66 mg/24 h in the perazine group, and significantly different from the results obtained in the control group: 185 mg/24 h. In contrast the urinary excretion of the unchanged phenazone increased from 29 to 40 mg/24 h under perazine. The results are interpreted to demonstrate inhibition of drug hydroxylation in the liver by perazine treatment.

[Thin-layer chromatographic determination of plasma levels of tricyclic psychopharmacological drugs: first results on their relationship to the clinical activity of neuroleptics (author's transl)]. / Dünnschichtchromatographische Bestimmung von Plasmaspiegeln tricyclischer Psychopharmaka: Erste Ergebnisse über eine Beziehung zur klinischen Wirkung von Neuroleptika

Plasma levels of perazine, clozapine, amitriptyline and imipramine and of their demethylated metabolites can be measured in patients receiving therapeutic doses by UV reflectance photometry of thin-layer chromatograms of plasma extracts, Large inter-individual variations were observed in unselected psychiatric patients treated with comparable doses. An investigation into the relationship between plasma levels and therapeutc effect in acutely schizophrenic patients was carried out for perazine and clozapine. With perazine, a group of patients exhibiting an unsatisfactory response had a tendency to show lower plasma levels than a group with a good response; in some patients of the former group, increase of the dose with concomitant increase of the plasma level led to a satisfactory therapeutic effect. In patients treated with clozapine, such a relationship could not be demonstrated.

Measurement of plasma levels of tricylic psychoactive drugs and their metabolites by UV reflectance photometry of thin layer chromatograms.

A method has been developed for the determination of perazine, clozapine, imipramine and amitriptyline and their demethylated metabolites in plasma. Other metabolites measured were perazine sulfoxide and the N-oxides of clozapine and perazine, the latter two following their reduction to the parent drugs with ascorbic acid. 10-Hydroxynortriptyline was identified as an amitriptyline metabolite in plasma. The general procedure included extraction of alkalinized plasma samples (3 - 6 g) with benzene or toluene and thin layer chromatography of the extracts, followed by reflectance photometry of the plates at appropriate wave lengths in ultraviolet light. Spots of questionable identity were further characterized by two-dimensional chromatography and by colour reactions. Therecoveries of compounds added in therapeutic concentrations were between 70 and 98 %. The limits of detectability were 5 - 10 ng/g plasma.

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.