Ursula Breyer

Perazine, chlorpromazine and imipramine as inducers of microsomal drug metabolism.

SummaryMale rats were treated orally for 7 days with perazine, chlorpromazine, imipramine or phenobarbital. Isolated liver microsomes were tested for their metabolic activities towards perazine, ethylmorphine and aniline. N-Demethylation of perazine and ethylmorphine was increased 2–3.5 fold by all pretreatments. Aromatic hydroxylation of perazine was decreased in microsomes from pretreated animals, whereas aniline hydroxylation was enhanced even more by perazine and imipramine than by phenobarbital. The yield of perazine sulfoxide was increased by phenobarbital treatment only. Perazine N-oxide formation was reduced by treatment with psychoactive drugs to 75–90% of control values and by phenobarbital to less than 50%. The microsomal cytochrome P-450 concentration was slightly elevated by perazine and substantially by chlorpromazine and imipramine treatment. The tricyclic drugs investigated are potent inducers of the drug-metabolizing enzyme system, the induction pattern differing in some respects from that seen after phenobarbital.

Formation of identical metabolites from piperazine- and dimethylamino-substituted phenothiazine drugs in man, rat and dog

Abstract Degradation of the piperazine ring in the phenothiazine drugs perazine, trifluoperazine, fluphenazine, prochlorperazine and perphenazine in vivo leads to the formation of γ-(phenothiazinyl-10)-propylamine (PPA) and of its ring-substituted analogues CF 3 -PPA and Cl-PPA. The sulfoxides of these metabolites have been identified as urinary biotransformation products in patients ingesting perazine or fluphenazine, in rats treated chronically with perazine, trifluoperazine, prochlorperazine or perphenazine, and in a dog given fluphenazine. The structures of the compounds have been confirmed by mass spectrometry. The primary amines are also known metabolites of dimethylamino-substituted phenothiazines, since PPA results from didemethylation of promazine, and CF 3 -PPA and Cl-PPA (= nor 2 -chlorpromazine) are formed from triflupromazine and chlorpromazine, respectively.

Metabolism of the phenothiazine drug perazine by liver and lung microsomes from various species

The oxidative metabolism of perazine was studied in vitro, using solvent extraction and thin layer chromatography followed by spectrophotometry for determination of the metabolites. Liver microsomes from rats, rabbits, pigs, guinea-pigs and cats and lung microsomes from rats, rabbits and pigs served as the enzyme sources. Kinetics of N-oxidation, N-demethylation, sulfoxidation and aromatic hydroxylation were measured with liver microsomes. Demethylation, sulfoxidation and aromatic hydroxylation underlie a substrate inhibition already at a perazine concentration of 1 mM, whereas N-oxidation usually is maximal with 2 mM perazine and starts to be inhibited at 4 mM perazine. In the concentration range tested (0·25-8 mM perazine) the N-oxide is always the major metabolite. Excessive N-oxidation has been observed in liver microsomes from individual pigs. Lung microsomes form substantial quantities of perazine N-oxide only, while other metabolites are produced to a negligible extent. An extremely high capacity for perazine N-oxidation was observed with rabbit lung microsomes, whereas microsomal preparations from rat and pig lungs N-oxidize perazine at a slower rate.

Metabolism of trifluoperazine, fluphenazine, prochlorperazine and perphenazine in rats: In vitro and urinary metabolites

Abstract In vitro and in vivo metabolites of trifluoperazine, fluphenazine, prochlorperazine and perphenazine were isolated by solvent extraction and thin layer chromatography and quantified by u.v. spectroscopy. In liver microsomes from male rats all four drugs underwent N -dealkylation. N -oxidation, sulfoxidation and aromatic hydroxylation. The relative rates of these reactions depended on the substrate concentration, N -oxidation being favoured at higher concentrations. N -Demethylation of trifluoperazine proceeded faster than removal of the hydroxyethyl group from fluphenazine which led to the same metabolite N [γ-(2-trifluoromethyl-phenothiazinyl-10)-propyl] piperazine. The same applied to the dealkylation of prochlorperazine and perphenazine. Following oral administration of 10 mg/kg of the drugs, male rats excreted 1.8−4 per cent of the dose within the first 12 hr in urine in the form of the sulfoxide and the N -dealkylated sulfoxide. In vivo , too, the N -hydroxyethyl group was removed to a smaller extent than the N -methyl group. N -Oxides were not detected in urine at this dose level, but when 25 or 50 mg/kg prochlorperazine were administered, rats excreted small amounts of the N -oxide.

Accumulation and elimination of a novel metabolite during chronic administration of the phenothiazine drug perazine to rats

Male rats were given perazine (methyl-piperazinyl-propyl-phenothiazine) per os in varying doses and for different periods of time. Liver, lung, kidney, spleen and brain tissue were analyzed for their content of perazine and three metabolites by means of extraction and thin layer chromatography followed by u.v. spectroscopy. A metabolite resulting from piperazine ring cleavage, N-[γ-phenothiazinyl-(10)-propyl]-ethylenediamine (PPED), was found to accumulate in all tissues in a dose- and time-dependent fashion. After administration of 25 or 50 mg/kg perazine for 7 days or longer, it was the only or the most abundant metabolite present in tissues. With a dose of 2 × 50 mg/kg daily, high concentrations of desmethyl perazine (DMP) were attained in lung, while PPED was the major metabolite in the other organs studied. Small quantities of perazine and γ-[phenothiazinyl-(10)]-propylamine were also present. After termination of a treatment with high perazine doses, perazine and DMP levels declined rapidly in all tissues (half-life < 5 hr). In contrast, PPED concentrations in liver decreased with a half-life of approximately 30 hr, and in extrahepatic tissues there was a transient increase followed by a decline with a half-life of more than 2 days. In these tissues PPED was still detectable 2 weeks after the last perazine dosage. These findings and the subcellular distribution in liver, characterized by a distinct concentration in mitochondria, suggest a strong binding of PPED to membrane proteins and/or lipids. PPED formation from perazine has also been demonstrated in the rabbit and the mouse. Its biosynthesis from DMP could be shown in the rat and the mouse.

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.

Absorption and metabolism of the phenothiazine drug perazine in the rat intestinal loop

Abstract Jejunal loops of male rats were instilled with [ 35 S]perazine and venous Wood from the loops was collected. Plasma, erythrocytes, intestinal wall and intestinal contents were analysed for perazine and its metabolites by reverse isotope dilution; purification to constant specific radioactivity was carried out by thin-layer chromatography. Within 60 min, 57 per cent of the material appeared in blood, more than four-fifths in the form of unchanged perazine. The principal metabolites present in plasma were 3-hydroxyperazine glucuronide and perazine sulfoxide; besides the sulfoxide, red cells contained small quantities of desmethyl perazine. This metabolite was predominantly located in the intestinal wall which contained a total of 17 per cent of the administered radioactivity, mostly as unmetabolized perazine. Another 17 per cent was found in the intestinal contents and here the proportion of perazine sulfoxide -was one-third. Besides perazine as the major compound small amounts of hydroxyperazine glucuronide and desmethyl perazine and traces of perazine N -oxide were present in the intestinal lumen.

Cerebrospinal fluid electrolyte disturbances in neurological disorders With special reference to inorganic phosphate

UNDER NORMAL CONDITIONS, electrolyte concentrations in cerebrospinal fluid are kept constant within narrow limits. This applies to the cations1-5 as well as to chloride.6 Only for phosphate relatively large normal ranges have been reported.7-11 Since rapid exchange of inorganic phosphate between blood and cerebrospinal fluid has been demonstrated in anima1sl2J3 and man14 (and in animals also with brain), an active transport system must exist which participates in establishing the normal level of phosphate. This study is aimed at a more complete survey of the pathological conditions which lead to an alteration of the ionic composition of cerebrospinal fluid, since this should help to understand the pathophysiology of derangements from the normal concentrations.

Urinary metabolites of 10-[3′-(4″-methyl-piperazinyl)-propyl]-phenothiazine (perazine) in psychiatric patients

SummaryThe urinary excretion of perazine metabolites was studied in schizophrenic patients during the first weeks after initiation of perazine treatment. Quantitative determinations of 9 metabolites did not reveal important inter-individual differences in metabolite patterns. In all those patient who had not been intensively pretreated with other phenothiazines, a marked increase in the ratio of demethylation products to the corresponding N-methyl compounds was oberved between the first and fourth week of treatment. The hypothesis of an induction of a demethylating enzyme by perazine is discussed.

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.