Kinetics of [3H]trifluoperazine in bile fistula rats.

1. Anaesthetized male rats with a bile fistula received 12-3 micron mol/kg [9-3H]tri-fluoperazine into the tail vein, and the biliary excretion of total radioactivity, unchanged drug and phenolic glucuronides was followed for 8 h. 2. About half of the administered radioactivity apeared in bile within 8 h;80% of the biliary metabolites were unextractable even after beta-glucuronidasearylsulphatase hydrolysis; about 10% were glucuronides of 7-hydroxytrifluoperazine and its N-demethylated analogue; approx. 0-6% of the excreted radioactivity was unchanged drug. 3. A more rapid excretion, but a similar metabolite pattern, was observed when the drug was administered into the portal vein and bile was collected for 2 h. 4. Rats pre-treated with trifluoperazine per os for 3 weeks and then given the radioactive dose into the tail vein excreted increased quantities of the demethylated phenol glucuronide, while the other metabolities remained unchanged.

Metabolism and disposition of trifluoperazine in the rat. I. A thin-layer chromatographic method for the measurement of trifluoperazine and its metabolites in rat tissues.

A method has been developed for quantitative measurement of trifluoperazine and its metabolites, 7-hydroxytrifluoperazine and desmethyltrifluoperazine, in rat organs. Trifluoperazine sulfoxide could also be assayed, but it proved to represent a very minor part only of total biotransformation products in tissues. Alkalinized tissue homogenates were extracted with di-isopropyl ether. Following removal of the bulk of lipids, the compounds to be quantitated were separated by thin-layer chromatography and measured by ultraviolet reflectance photometry on the plates. In recovery experiments, the method proved to possess a high reproducibility. The sensitivity limit for quantitative determination was about 0.1 nmol per extract, and the limit of detectability was 0.025-0.05 nmol. The applicability of the method was shown by analyzing the tissues of rats that had received 12.3 micronmol of trifluoperazine, ip, per kg.

The rat brain as a "deep compartment" in the kinetics of a common metabolite of prochlorperazine and perphenazine.

N-[gamma-(2-Chlorophenothiazin-10-yl)propyl]ethylenediamine (Cl-PPED), a common metabolite of prochlorperazine and perphenazine, was orally administered to male rats at a dose of 50 mg/kg, and its concentrations in plasma, liver, lung, kidney, and brain were followed from 6 hr to 40 days after dosage. Small quantities were measured by two-dimensional thin-layer chromatography of a fluorescent derivative and in situ fluorometry of the chromatograms. The kinetic behavior of Cl-PPED in brain differed from that in other tissues in that the concentration maximum was achieved later and the elimination half-life was distinctly longer (8 days vs. 1.2-3 days). Cl-PPED was evenly among the three major brain regions. Subcellular fractionation of liver and brain revealed preferential localization in mitochondria.

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.

[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.

Thin-layer chromatographic determination of barbiturates and phenytoin in serum and blood.

A method is described for the measurement of blood, serum and/or plasma levels of hexobarbital, phenobarbital, cyclobarbital and phenytoin by ultraviolet reflectance photometry on thin-layer chromatograms. The lowest concentrations measured were 0.3-0.7 mug/ml. The accuracy was similar to that of gas chromatographic procudures. For phenytoin determinations 5-(p-methylphenyl)-5-phenylhydantoin may be used as internal standard. The method has been applied to clinico-pharmacological assays, to the measurement of cyclobarbital elimination in man following a therapeutic dose, and to the study of phenobarbital kinetics in rats using serial blood samples.

Tissue metabolites of trifluorperazine, fluphenazine, prochlorperazine, and perphenazine. Kinetics in chronic treatment.

Repeated oral treatment of male rats with piperazine-substituted phenothiazine drugs in doses of 25 mg/kg or more daily led to an accumulation of metabolites containing an ethylenediamine group instead of the piperazine ring. These products of ring degradation with and without removal of the N-alkyl group were found, together with the parent drugs and their N-dealkylated metabolites, in liver, lung, kidney, and spleen, as well as in brain when high doses were administered. After termination of treatment, the ethylenediamine derivatives were eliminated more slowly than were their congeners containing the intact piperazine ring. Parallel observations were made in dogs given fluphenazine in daily doses of up to 40 mg/kg. Quantitative differences were observed in the relative amounts of mono- and disubstituted ethylenediamine metabolites accumulated in rat tissues during treatment with the various drugs; the proportion of the monosubstituted product formed by N-dealkylation and ring cleavage declined in the following order: perazine, prochlorperazine, trifluoperazine, fluphenazine, perphenazine. Condensation products of the ethylenediamine derivatives with formaldehyde were split in the extraction procedure used.