Separation of enantiomers of derivatised or underivatised propranolol by means of high-performance liquid chromatography.
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Chromatography, High Pressure Liquid↗
Biomedical subjects
K K Midha
Publications and source records attributed to K K Midha.
Neuroleptic plasma level may predict response in patients who meet a criterion for improvement.
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Fluphenazine↗
Variation in the single dose pharmacokinetics of fluphenazine in psychiatric patients.
The single dose pharmacokinetics of fluphenazine (2 x 5 mg tablets, Prolixin) were studied in 21 drug free male psychiatric patients (12 black, 9 white). Plasma samples were harvested over a period of 48 h while the patients were on a strictly controlled diet. The results showed wide interpatient variations in all pharmacokinetic parameters including Cmax, AUC, apparent oral clearance, and elimination half-life. It was determined for each of these parameters that the geometric mean gave a better estimate of central tendency than the corresponding arithmetic mean and the distribution was skewed and leptokurtotic. There was no significant difference between blacks and whites in any pharmacokinetic parameter examined. Considerable variations and marked undulations in the elimination portion of the plasma concentration versus time profiles were evident, possibly indicating biliary recycling of the drug. These undulations made it difficult to determine elimination rate constants for several of the patients. Hydrolysis or plasma samples from one patient demonstrated that the conjugate(s) of fluphenazine was present in three to four times the concentration of the unchanged drug.
Adult↗
A pharmacokinetic study of trifluoperazine in two ethnic populations.
The single dose pharmacokinetics of trifluoperazine (5 mg, Stelazine) were investigated in black (n = 25) and white (n = 32) healthy male subjects. Plasma samples were harvested over 24 h and analysed by a GLC-MS method. There were wide intersubject variations in all pharmacokinetic parameters examined, including Cmax, AUC, apparent oral volume of distribution at steady state, and elimination half-life. For each of these parameters the distribution was positively skewed in both blacks and whites and the geometric mean gave a better estimate of central tendency than the corresponding arithmetic mean. In all pharmacokinetic parameters examined there was no significant difference detected between black and white subjects or between smokers and non-smokers.
Adolescent↗
Radioimmunoassay for fluphenazine sulfoxide in human plasma.
Antisera to fluphenazine sulfoxide were raised in New Zealand white rabbits to an immunogen synthesized by covalent linkage of bovine serum albumin to 10-[[3-[4-(4-carboxybutyl)-1-piperazinyl] propyl]]-2-trifluoromethyl-10H-phenothiazine 5-sulfoxide. With use of an antiserum, a radioimmunoassay for fluphenazine sulfoxide was developed that is able to quantitate 0.156 ng ml-1 using only a 200 microliter plasma sample with a coefficient of variation less than 5%. The antiserum had negligible cross-reactivities to fluphenazine (less than 1%) and its important metabolites, such as fluphenazine N4'-oxide (1%), 7-hydroxyfluphenazine (less than 1%), and N4'-deshydroxy-ethylfluphenazine (1%). The cross-reactivities with structurally similar phenothiazine 5-sulfoxides, such as those of trifluoperazine, prochlorperazine, perphenazine, and N4'-deshydroxyethylfluphenazine, were considerable, such that the antiserum can be used to develop a quantitative radioimmunoassay for any of these compounds. The reported radioimmunoassay was found to be suitable and adequate to quantitate fluphenazine sulfoxide in the plasma of patients treated with oral or intramuscular fluphenazine.
Fluphenazine↗
An ultrasensitive method for the measurement of haloperidol and reduced haloperidol in plasma by high-performance liquid chromatography with coulometric detection.
A new analytical method has been developed for the simultaneous quantitation of haloperidol and reduced haloperidol in plasma. The method is based on high performance liquid chromatography (HPLC) with coulometric detection. The extraction and sample clean up procedures are simple and rapid to execute, yet yield chromatograms virtually free of interference from endogenous plasma constituents, such that the extraordinary sensitivity of the coulometric detector can be exploited fully. The detection limits for haloperidol and reduced haloperidol are 20 pg/ml plasma, and the limits of quantitation are 50 pg/ml for both drug and metabolite. Standard curves were linear down to 50 pg/ml with coefficients of variation of less than 7.0% at the limits of quantitation. The method was applied to the study of the plasma levels of haloperidol and reduced haloperidol in two healthy subjects. It was possible to monitor the plasma levels of haloperidol for at least 96 h (4 days) after the administration of a 5-mg oral dose of haloperidol. It was also possible to monitor reduced haloperidol levels over 96 h in one subject, although the metabolite was not detectable in the plasma of the other at any stage.
Chromatography, High Pressure Liquid↗
Development of a radioimmunoassay procedure for sulforidazine and its comparison with a high-performance liquid chromatographic method.
A radioimmunoassay (RIA) procedure for the determination of sulforidazine in human plasma was developed using an antiserum raised in rabbits immunized with N-(2-carboxyethyl)desmethylsulforidazine-porcine thyroglobulin conjugate. The RIA procedure can measure as low as 40 pg of sulforidazine in a 200-microliter human plasma sample with a coefficient of variation of less than 6%. The antiserum did not show any marked cross reaction with any available potential cross reactant. Also, there were no significant differences between the concentrations of sulforidazine determined in the presence or absence of thioridazine and/or mesoridazine. This RIA procedure was compared with a high performance liquid chromatographic (HPLC) method by determining concentrations of sulforidazine in plasma samples from human volunteers over 72 h after administration of single 50-mg oral doses of thioridazine hydrochloride. The two methods showed a good correlation for the assay values (n = 55; r2 = 0.926) and the slope of the regression line was not significantly different from 1.0 (p greater than 0.30 when RIA values were plotted on the gamma-axis and HPLC values on the chi-axis; p greater than 0.30 when HPLC values were plotted on the gamma-axis and RIA values on the chi-axis). The plot of the differences between these two assay values against the average of the assay values showed that the differences were independent of the concentration range studied. Also, statistically favorable comparisons were obtained for area under the plasma concentration-time curve to 48 h (AUC48(0)), Cmax, and Tmax calculated from the data obtained by the two methods.
Animals↗
Clinical modulation of doxorubicin resistance by the calmodulin-inhibitor, trifluoperazine: a phase I/II trial.
Drug resistance to chemotherapy agents such as doxorubicin appears to be an important cause of therapeutic failure in cancer treatment. Based on preclinical information demonstrating that the phenothiazine calmodulin-inhibitor trifluoperazine can enhance retention and cytotoxicity of doxorubicin in resistant cells, a phase I/II trial of the combination was performed to determine the maximally tolerated dose (MTD) of trifluoperazine that could be administered with doxorubicin. Patients with intrinsic (no previous response) and acquired (previous response with relapse) doxorubicin resistance were eligible. Doxorubicin was administered as a 96-hour continuous infusion (60 mg/m2) on days 2 through 5. Trifluoperazine was administered in divided doses orally on days 1 through 6, with dose escalation from 20 to 100 mg/d. Thirty-six patients were evaluable. The MTD of trifluoperazine was 60 mg/d, with dose-limiting toxicity being extrapyramidal side effects. No alteration of doxorubicin toxicity was observed. Seven of the 36 patients responded (one complete response [CR], six partial responses [PR]), with seven of 21 patients having acquired resistance, and zero of 15 with intrinsic resistance demonstrating responses. Doxorubicin plasma levels were not affected by trifluoperazine, and the maximal trifluoperazine plasma levels achieved were 129.83 ng/mL. This trial demonstrates the combination of trifluoperazine and doxorubicin is well tolerated, and the schedule recommended for phase II trials is doxorubicin, 60 mg/m2 (continuous infusion) days 2 through 5, and trifluoperazine, 15 mg four times per day orally days 1 through 6. Continued investigation of this combination is indicated for patients with acquired doxorubicin resistance.
Adult↗
S-oxidation of thioridazine to psychoactive metabolites: an oral dose-proportionality study in healthy volunteers.
Thioridazine has two major active metabolites, which are formed from S-oxidation of its 2-methylthio group; the sulphoxide, mesoridazine, and the sulphone, sulforidazine. Dose proportionality of the three compounds was investigated for the first time in 11 males after administration of three single oral doses (25, 50, and 100 mg) of thioridazine hydrochloride separated in each case by two weeks. Based on the plasma concentrations of the three analytes over 72 h following each dose, large intersubject variabilities in such parameters as AUCot and Cmax were observed for each of the three compounds. The relationships between dose and parameters such as AUCot and Cmax for each analyte were described by an equation for a straight line (r2 greater than or equal to 0.8). However, the mean apparent distribution and elimination rate constants for thioridazine and mesoridazine and the mean apparent oral clearance for thioridazine decreased significantly with increasing dose, suggesting non-linearity in the elimination of thioridazine at high dose.
Adult↗
The metabolism of chlorpromazine N-oxide in the rat.
1. The metabolism of chlorpromazine N-oxide was studied in female rats after a 20 mg/kg single oral dose. 2. Metabolites identified in both urine and faeces were chlorpromazine, 7-hydroxychlorpromazine, chlorpromazine sulphoxide, N-desmethylchlorpromazine and N-desmethylchlorpromazine sulphoxide. 3. Metabolites were separated by h.p.l.c. or g.l.c. prior to mass spectrometric analysis. The structures of the metabolites were confirmed by direct comparison of their mass spectra and chromatographic behaviours with those of authentic compounds. 4. Chlorpromazine N-oxide and any metabolite which retained the intact N-oxide function, such as chlorpromazine, N,S-dioxide, could not be identified in any of the extracts. 5. When 3H-chlorpromazine N-oxide was administered under the same conditions; approximately twice as much radioactivity was excreted in the faeces (52.1 +/- 9.7%) as in the urine (26.9 +/- 7.2%).
Administration, Oral↗
Persistence of fluphenazine in plasma after decanoate withdrawal.
We discontinued fluphenazine decanoate using a double-blind, crossover random order design, in 12 recent onset clinically stable schizophrenics who had been given fluphenazine decanoate 12.5 mg intramuscularly every 2 weeks for at least 1 year prior to drug withdrawal. Each condition (drug or placebo) lasted 12 weeks. Using a radioimmunoassay verified by comparison to a gas chromatographic-mass spectrometric method, plasma fluphenazine levels were measured every 2 weeks during drug continuation and drug withdrawal conditions. No patient relapsed over the 24-week period of the study. Mean fluphenazine levels between drug continuation and withdrawal conditions showed a progressively larger difference over time, although significant differences were not seen until week 8. By week 12 after drug withdrawal, 33% of subjects still showed notable plasma fluphenazine levels. On the basis of our preliminary findings, we suggest that 2-week intervals between injections may be too short and that wider intervals may achieve similar clinical results.
Adult↗
Sensitive and specific high-performance liquid chromatographic assay for the quantification of sulforidazine and two diastereomeric sulforidazine-5-sulfoxide metabolites in plasma.
A sensitive and specific procedure using high-performance liquid chromatography for the quantification of sulforidazine and two diastereomeric sulforidazine-5-sulfoxide metabolites in plasma was developed. Sulforidazine was first extracted from basified plasma using a mixture of pentane and 2-propanol. Sulforidazine-5-sulfoxide metabolites were then extracted from the same basified plasma using a second solvent mixture consisting of methylene chloride, pentane and 2-propanol. Each organic extract was subsequently back-extracted separately with 0.1 M hydrochloric acid, basified and re-extracted with the original solvent mixtures. In order to avoid interferences due to hydroxylated metabolites co-eluting with sulforidazine-5-sulfoxides in the more polar extract, this extract was derivatized with N-methyl-(tert.-butyldimethylsilyl) trifluoroacetamide. The two extracts were separately chromatographed on a narrow-bore nitrile column using ultraviolet detection. The quantification limits for sulforidazine and two diastereomeric sulforidazine-5-sulfoxide metabolites were 1.0 ng/ml with mean intra-assay coefficients of variation less than 10%. These methods were applied to the analysis of plasma from a dog following the administration of a single oral dose (25 mg of the base) of sulforidazine hydrochloride.
Animals↗
Prolonged pharmacologic activity of neuroleptic drugs.
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Antipsychotic Agents↗
Influence of urinary pH on the disposition of methoxyphenamine and three metabolites in humans.
The disposition of methoxyphenamine (o-methoxy-N,alpha-dimethylphenethylamine) and three of its metabolites was studied in five healthy volunteers on three occasions, with the urine pH separately under uncontrolled, acidic, and basic conditions. All five volunteers were extensive metabolizers of debrisoquine and methoxyphenamine, the latter with respect to O-demethylation and aromatic 5-hydroxylation. The plasma peak concentration and the area under the curve of methoxyphenamine from 0 to infinity did not differ significantly during the three phases of the study. However, on the average, its renal clearance increased by fivefold and its plasma terminal half-life decreased by twofold in the acidic as compared with the alkaline urine condition. The urinary excretions of methoxyphenamine and its metabolites N-desmethylmethoxyphenamine and O-desmethylmethoxyphenamine were significantly enhanced in the uncontrolled pH and the acidic urine conditions as compared with the alkaline urine condition. By contrast, the urinary excretion of the 5-hydroxymethoxyphenamine metabolite was not significantly affected by urinary pH variations. The mean urinary excretion ratios methoxyphenamine: O-desmethylmethoxyphenamine and N-desmethylmethoxyphenamine: O-desmethylmethoxyphenamine did not differ significantly during the three phases of the study, whereas the methoxyphenamine:5-hydroxymethoxyphenamine and N-desmethylmethoxyphenamine:5-hydroxymethoxyphenamine ratios were significantly altered during the alkaline phase as compared with the other two phases. Therefore, the ratios in terms of O-desmethylmethoxyphenamine are recommended for phenotyping individuals when using methoxyphenamine as a metabolic probe.
Adult↗
Radioimmunoassay for the N-oxide metabolite of chlorpromazine in human plasma and its application to a pharmacokinetic study in healthy humans.
Antibodies specific to chlorpromazine N-oxide (CPZNO) were produced in rabbits immunized with a hapten-bovine serum albumin conjugate, which was prepared by linking the 7-position of the phenothiazine ring of the metabolite to the protein via a 4-carbon bridge. An extraction radioimmunoassay (RIA) was developed using this antiserum and shown to have adequate sensitivity and specificity for determination of plasma concentrations of CPZNO in the presence of chlorpromazine (CPZ) and its major metabolites. It was used together with the previously developed RIAs for CPZ, chlorpromazine sulfoxide (CPZSO), and 7-hydroxychlorpromazine (7-OHCPZ) to study the pharmacokinetics of CPZ and these metabolites in five healthy volunteers after they received a single 50-mg oral dose of CPZ. It is interesting to note that peak plasma concentrations of CPZNO were considerably higher than CPZ, and the apparent elimination half-lives of this metabolite were shorter than those of CPZ.
Adult↗
The sulfoxidation of fluphenazine in schizophrenic patients maintained on fluphenazine decanoate.
Highly sensitive radioimmunoassays were applied to study the sulfoxidation of fluphenazine in 30 schizophrenic patients maintained on either 5 mg or 25 mg fluphenazine decanoate by intramuscular injection every 14 days over a period of 6 months. The presence of the sulfoxide metabolite was detected in all but one of the patients, such that 97% of the 340 plasma samples analysed contained the metabolite. Interpatient variations in plasma levels of fluphenazine, fluphenazine sulfoxide, and in drug to metabolite plasma level ratios were several fold higher than the corresponding intrapatient variations at both dosages. There were statistically significant tendencies for mean plasma fluphenazine levels to rise and mean plasma sulfoxide levels to fall over the 6-month period of study among patients on the high dose, consistent with our previously reported observation that it takes 3-6 months to establish a steady state of fluphenazine with this dosage regimen. By contrast, there were no statistically significant changes in mean plasma levels of either fluphenazine or its sulfoxide in patients on the low dose. Nevertheless, there was a significant rise in fluphenazine to fluphenazine sulfoxide mean plasma level ratios in both dosage groups. It is difficult to assess the significance of the changes in the drug to metabolite ratios with time, since there are no kinetic data on the phase II metabolism (conjugation) of fluphenazine or fluphenazine sulfoxide. This study shows that sulfoxidation is an important major pathway in the metabolism of intramuscularly-administered fluphenazine, and implies that metabolic sites other than gut wall are also involved in the process.
Fluphenazine↗
Methoxyphenamine O-demethylase and 5-hydroxylase: a GLC-ECD assay to study their activities and their inhibition by debrisoquine and sparteine.
A GLC-ECD method is described for the determination of the O-desmethyl, N-desmethyl and aromatic 5-hydroxy metabolites of methoxyphenamine in liver homogenates. The O-desmethyl and 5-hydroxy metabolites are deficient in poor metabolizers of debrisoquine and sparteine and the Dark Agouti rat model of this human phenotype. The present analytical method can be useful in determining methoxyphenamine O-demethylase and 5-hydroxylase activities as well as identifying those substrates which inhibit these and are worthy of further study.
Animals↗
Synthesis and properties of haptens for the development of radioimmunoassays for thioridazine, mesoridazine, and sulforidazine.
For the separate development of radioimmunoassay procedures for thioridazine and its two major active metabolites, mesoridazine and sulforidazine, three haptens, respectively, 2-methylthio-, 2-methylsulfinyl-, and 2-methylsulfonyl-substituted 10-[2-[1-(2-carboxyethyl)-2-piperidinyl]ethyl]-10H-phenothiazine, were synthesized and characterized. Thioridazine hapten was coupled to bovine serum albumin, whereas the haptens for mesoridazine and sulforidazine were coupled to porcine thyroglobulin. The number of hapten residues per mole of carrier protein was determined in each case by an ultraviolet spectrophotometric method. Polyclonal antibodies to each hapten-protein conjugate were obtained in rabbits, and titers of the antisera were checked by evaluating their binding characteristics to the appropriate tritiated analyte. A hapten for the ring sulfoxide metabolite of thioridazine was also synthesized.
Animals↗