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Biomedical subjects

E M Hawes

Publications and source records attributed to E M Hawes.

At least 91 records · Page 5Linked to original sources
PubMed1985

Metabolism of methoxyphenamine in extensive and poor metabolizers of debrisoquin.

Urine and plasma concentrations of methoxyphenamine (MP) and three of its metabolites were determined after a single oral 60.3 mg dose of MP hydrochloride to healthy subjects of known debrisoquin (D) phenotype. Urine was collected from five extensive (EM) and five poor (PM) metabolizers of D for 12 hours and analyzed after treatment with beta-glucuronidase/sulfatase. There were marked interphenotype differences in the total urinary excretion of O-demethylmethoxyphenamine (ODMP) and 5-hydroxymethoxyphenamine (5HMP), as well as in MP/ODMP and MP/5HMP ratios. In contrast, the urinary output of N-demethylmethoxyphenamine (NDMP) or MP/NDMP ratios showed no interphenotype differences. Plasma data from two EMs and two PMs showed that the mean values for maximum concentration t1/2, and total AUC for MP were two-, three-, and sixfold greater, respectively, in PMs than in EMs. The plasma levels of ODMP and 5HMP were higher in EMs than in PMs, whereas the converse was true for NDMP. Thus, O-demethylation and aromatic 5-hydroxylation of MP are defective in PMs of D, resulting in increased MP and NDMP plasma levels. The form of cytochrome P-450 involved in the N-demethylation of MP is different from that responsible for O-demethylation and aromatic 5-hydroxylation.

Adult↗
PubMed1985

Therapeutic monitoring of chlorpromazine I: Pitfalls in plasma analysis.

Pooled plasma from healthy volunteers was spiked with pure, synthetic chlorpromazine (CPZ), chlorpromazine sulfoxide (CPZSO), or chlorpromazine N-oxide (CPZNO), and then made alkaline with either sodium hydroxide or sodium carbonate. The samples were allowed to stand at room temperature for various timed intervals before extraction with organic solvent. It was found that CPZNO was reduced to CPZ in plasma made alkaline with sodium hydroxide, but not in protein-free buffer solution at high pH nor in plasma made alkaline with sodium carbonate. The reaction appears to take place through reducing equivalents generated by the action of sodium hydroxide on plasma proteins. Thus, apparent concentrations of CPZ in plasma from patients were elevated by as much as 343% when sodium hydroxide was used compared with concentrations in aliquots of the same plasma samples alkalinized with sodium carbonate. The amount of CPZ produced from CPZNO depends on the type of extraction procedure employed as well as on the quantity of sodium hydroxide added to the plasma. By contrast, no interconversion between CPZ and CPZSO or CPZNO and CPZSO was observed in plasma alkalinized and extracted under any of the conditions tested.

Chlorpromazine↗
PubMed1985

Therapeutic monitoring of chlorpromazine II: Pitfalls in whole blood analysis.

Pooled whole blood from healthy volunteers was spiked with pure, synthetic chlorpromazine, chlorpromazine sulfoxide, or chlorpromazine N-oxide and then made alkaline with either sodium hydroxide or sodium carbonate. The addition of alkali causes lysis of red cells, the contents of which spill into the plasma. The lysed samples were allowed to stand at room temperature for various timed intervals before extraction with organic solvents and analysis by high performance liquid chromatography. It was found that a portion (10-14%) of the chlorpromazine spike was oxidised to chlorpromazine sulfoxide, whether the blood was made alkaline with sodium hydroxide or sodium carbonate. Chlorpromazine N-oxide added to whole blood was entirely destroyed in the presence of alkali. The chlorpromazine N-oxide was rapidly reduced to chlorpromazine, a portion of which subsequently underwent oxidation to chlorpromazine sulfoxide. We have found that chlorpromazine N-oxide resides almost entirely in the plasma with only a small portion (less than 4%) distributed into the red cells. Hence, it is essential that red cells and plasma be separated before analysis. Chlorpromazine and chlorpromazine N-oxide can then be extracted from plasma by a method that does not lead to reduction of chlorpromazine N-oxide. Alkaline extraction methods must be avoided in the analysis of chlorpromazine in the red cell fraction.

Chlorpromazine↗
PubMed1985

Methoxyphenamine metabolism in rat models of human debrisoquine phenotypes.

The metabolism of the beta 2-adrenoceptor agent methoxyphenamine was investigated in rats of the Lewis and Dark Agouti strains, which are proposed models for human extensive and poor metabolizers of debrisoquine, respectively. Following oral ingestion of 20 mg kg-1 of methoxyphenamine, Dark Agouti excreted, on the average, significantly more methoxyphenamine and less O-demethylmethoxyphenamine and 5-hydroxymethoxyphenamine in 0- to 24-h urine than Lewis. In contrast, the N-demethylation of methoxyphenamine showed no interphenotype differences between the two strains. It is possible that in rats, the form of cytochrome P-450, which controls the 4-hydroxylation of debrisoquine, may also control the O-demethylation and aromatic 5-hydroxylation of methoxyphenamine.

Animals↗
PubMed1984

Gas chromatographic quantitation of methoxyphenamine and three of its metabolites in plasma.

Sensitive gas chromatographic procedures for the determination of methoxyphenamine and three of its metabolites in plasma have been developed. The metabolites were measured using an electron-capture detector. This simple procedure is based on the precipitation of protein from a 1-ml plasma sample with 10% trichloroacetic acid, followed by aqueous derivatization with pentafluorobenzoyl chloride at pH 9.2 and a single-step cyclohexane extraction. The lower limit of detection for the N-desmethyl, O-desmethyl and aromatic 5-hydroxy metabolites of methoxyphenamine were 1.6, 3.1 and 2.2 ng ml-1, respectively, with coefficients of variation less than 10%. The poor electron-capture response of fluorinated derivatives of methoxyphenamine necessitated the use of nitrogen-phosphorus detection. Extractive derivatization with pentafluorobenzoyl chloride, without the need for protein precipitation, enabled quantitation of methoxyphenamine down to 3.8 ng ml-1 from a 2-ml aliquot of plasma. In a pilot study involving healthy volunteers who received a single oral dose of methoxyphenamine hydrochloride plasma concentration could be followed in all three subjects for at least 24, 32, 12 and 4 h for methoxyphenamine and the O-desmethyl, 5-hydroxy and N-desmethyl metabolites, respectively.

Adrenergic beta-Agonists↗
PubMed1984

Synthesis of deuterium-labeled fluphenazine.

The propylpiperazine side chain of fluphenazine has been labeled with two, four, and six deuterium atoms by lithium aluminum deuteride reduction of the appropriate ester or imide. The gamma-carbon of the propyl group was labeled with two deuterium atoms by reduction of 10- (2-methoxycarbonylethyl) -2-trifluoromethyl-10H-phenothiazine, while four deuterium atoms were incorporated into the piperazine ring by reduction of 10-[3-(3,5-dioxo-1-piperazinyl)propyl]-2-trifluoromethyl-10H-pheno thiazine. The latter reduction gave the d4-labeled N-deshydroxyethyl metabolite of fluphenazine.

Chemical Phenomena↗
PubMed1984

Radioimmunoassay for psychotropic drugs. III: Synthesis and properties of haptens for trifluoperazine and fluphenazine.

For the development of radioimmunoassay procedures for trifluoperazine and fluphenazine, three haptens, N-(2-carboxyethyl)desmethyltrifluoperazine, N-(4-carboxybutyl)desmethyltrifluoperazine, and 10-[3-(4-carboxyethylpiperazinyl)-3-oxopropyl]-2-trifluoromethyl-+ ++10H- phenothiazine, were synthesized and characterized. Each hapten was coupled to bovine serum albumin, and the number of hapten residues per mole of bovine serum albumin was calculated by UV spectrophotometric methods. Antibodies to each hapten-protein conjugate were developed in rabbits, and titers of the antisera were checked by evaluating their binding characteristics to the tritiated drug.

Animals↗
PubMed1984

Relative bioavailability of a commercial trifluoperazine tablet formulation using a radioimmunoassay technique.

The relative bioavailability of a new conventional tablet formulation (5 mg) of trifluoperazine dihydrochloride was studied in 24 healthy volunteers. Using a sensitive radioimmunoassay technique, plasma trifluoperazine concentrations were measured up until 24 h following ingestion of single 5-mg doses of trifluoperazine. The mean +/- SD for the peak concentration (Cmax), time to Cmax, area under the curve from 0 to 24 h (AUC240), and terminal elimination half-life following the administration of the test formulation were 2.15 +/- 1.07 ng/mL, 4.10 +/- 1.38 h, 21.04 +/- 11.92 ng X h/mL, and 9.5 +/- 7 h, respectively. Following the ingestion of the original trifluoperazine tablet formulation (5 mg) these same parameters were estimated to be 1.92 +/- 0.88 ng/mL, 4.02 +/- 1.10 h, 18.03 +/- 10.11 ng X h/mL, and 9.3 +/- 7 h, respectively. Large intersubject variations in Cmax and AUC240 were observed. The relative bioavailability of the test formulation was calculated to be 106.5 +/- 25.5%.

Adult↗
PubMed1984

Radioimmunoassay for the sulfoxide metabolite of trifluoperazine and its application to a kinetic study in humans.

Antibodies were produced in rabbits immunized with 10-[[3-[4-(2-carboxyethyl)-1-piperazinyl]-propyl]]-2 -trifluoromethyl-10H-phenothiazine sulfoxide-bovine serum albumin conjugate. The subsequently developed radioimmunoassay (RIA) procedure enables, for the first time, the quantitation of the sulfoxide metabolite of trifluoperazine in the plasma of humans after administration of therapeutic doses of trifluoperazine, in which 60 pg of the sulfoxide metabolite in 200 microL of plasma can be measured with a CV of less than 3%. Similar results were obtained by this assay with or without a benzene extraction step and also in the presence or absence of a large excess of trifluoperazine and suspected major metabolites of trifluoperazine. This RIA procedure, together with a previously developed RIA for trifluoperazine was used to directly determine plasma concentrations of trifluoperazine and its sulfoxide metabolite after administration of a single, low, oral dose of trifluoperazine to five healthy volunteers. The rapidly appearing, relatively high concentrations of the sulfoxide metabolite are indicative of presystemic sulfoxidation. The mean plasma elimination half-life for the sulfoxide metabolic of trifluoperazine was 5.8 +/- 1.3 h.

Humans↗
PubMed1984

Radioimmunoassay for trimeprazine in human plasma.

Antisera to trimeprazine were raised in New Zealand white rabbits to an immunogen synthesized by covalent linkage of bovine serum albumin to N-(2-carboxyethyl)desmethyltrimeprazine. By use of an antiserum, a radioimmunoassay for trimeprazine was developed that is able to quantitate 0.38 ng/ml-1 in a 200 microliter plasma sample with a coefficient of variation of approximately 12%. The antiserum did not cross-react with the supposedly pharmacologically inactive metabolite trimeprazine sulfoxide; however, the cross-reactivity with the supposedly active metabolite N-desmethyltrimeprazine is significant (49%). The radioimmunoassay was able to measure the drug and/or N-desalkyl metabolites in plasma samples obtained as late as 24 hr following administration of a single oral dose (10mg) of trimeprazine tartrate. Analysis of the same plasma samples by a published high-performance liquid chromatographic procedure gave values much lower than those obtained by the radioimmunoassay, indicating the N-desalkyl metabolites are produced significantly after trimeprazine oral administration.

Antibody Affinity↗
PubMed1983

Subnanogram determination of fluphenazine in human plasma by gas chromatography mass spectrometry.

A new gas chromatographic mass spectrometric procedure for the quantitation of fluphenazine in plasma is described. The method relies on the selected ion monitoring of fluphenazine (m/z 406.1563) and perphenazine (m/z 372.1299), the internal standard, after extraction from plasma with 5% isopropanol in n-pentane. Interferences by plasma constituents such as cholesterol are avoided by including an n-hexane wash. This wash step reduced the recovery of fluphenazine and to a greater extent perphenazine, however, it yielded an organic solution relatively free of any peaks with interfering ions. Prior to gas chromatographic mass spectrometric analysis the silyl derivatives of fluphenazine and perphenazine are prepared using N,O-bis(trimethyl-silyl)acetamide. This procedure allows for the quantitation of as low as 78 pg of fluphenazine per ml of plasma using 2.0 ml plasma aliquots with a coefficient of variation of 4.6%. The high specificity and sensitivity demonstrated by this method allows for the first time the monitoring of plasma concentrations of fluphenazine up to 32 h following a single oral dose of 5 mg of the drug.

Fluphenazine↗
PubMed1983

Synthesis of deuterium-labeled prochlorperazine.

The propylpiperazine side chain of prochlorperazine was labeled with two, four, or six deuterium atoms by lithium aluminum deuteride reduction of the appropriate amide. The isotopic purity of the products after correcting for chlorine isotopes was greater than 95.7%.

Deuterium↗
PubMed1983

Kinetics of oral fluphenazine disposition in humans by GC-MS.

The disposition of fluphenazine was investigated in six healthy volunteers following oral administration (5 mg). Using a sensitive and specific GC-MS procedure plasma fluphenazine concentrations were measured up until 32 h after drug administration. Peak plasma concentrations varied widely (range: 0.26-1.06 ng/ml) and were observed at 2.8 +/- 0.5 h following fluphenazine administration. The apparent terminal elimination half-life of fluphenazine was 33.1 +/- 8.1 h. The area under the plasma concentration-time curve differed widely between subjects (range: 7.1-28.6 ng/ml h) suggesting large interindividual differences in the extent of fluphenazine presystemic elimination.

Administration, Oral↗
PubMed1983

Development of radioimmunoassays for trifluoperazine and their application to metabolic studies of the drug.

Antisera to trifluoperazine have been raised in New Zealand white rabbits to several different types of immunogens, where there was variation in the length and nature of the side chain attached to the phenothiazine nucleus, as well as in the number of hapten residues coupled to bovine serum albumin. A radioimmunoassay for trifluoperazine has been developed which is capable of quantitating 0.3125 ng ml-1 in a 200 microliter plasma sample, with cross-reactivities to the sulfoxide, 7-hydroxy, and N-desmethyl metabolites of trifluoperazine of the order of less than 1, 11, and 12%, respectively. Some of the investigated antisera were applied to metabolic studies involving trifluoperazine, where it was demonstrated that N-desmethyltrifluoperazine, rather than 7-hydroxytrifluoperazine, was a major metabolite of trifluoperazine in plasma of a volunteer following administration of a single 5 mg oral dose.

Cross Reactions↗
PubMed1983

Radioimmunoassays for phenothiazine drugs and their major metabolites in plasma.

Radioimmunoassay procedures have been developed for some phenothiazine drugs and their major metabolites which are capable of quantitating 0.3 ng/ml or less in a 200 microliter plasma sample with a coefficient of variation less than 3%. They were developed with a view to their use in pilot investigations of plasma level versus clinical response correlations. The development of the procedures for trifluoperazine are described in this workshop. Antisera to trifluoperazine have been raised in New Zealand white rabbits to several different types of immunogens, where there was variation in the length and nature of the N-10 side chain attached to the phenothiazine nucleus, as well as in the number of hapten residues coupled to bovine serum albumin. An improved radioimmunoassay for trifluoperazine has been developed which showed cross-reactivities to the N-desmethyl and 7-hydroxy metabolites of trifluoperazine of the order of 12 and 11%, respectively, in comparison to the 26 and 24% cross-reactivity, respectively, for the same metabolites by a previously reported procedure.

Antipsychotic Agents↗
PubMed1983

Correlation of fluphenazine plasma levels versus clinical response in patients: a pilot study.

Five schizophrenic patients (diagnosed using Research Diagnostic Criteria) under treatment with intramuscular fluphenazine decanoate or oral fluphenazine dihydrochloride had serial plasma fluphenazine and plasma prolactin levels determined by a direct radioimmunoassay method. Clinical state was assessed utilizing the Global Assessment Scale and the Extrapyramidal Symptoms-Neurological Rating Scale. There was no correlation between clinical state and plasma fluphenazine or prolactin levels. All patients under treatment with the depot preparation remained clinically stable with serum fluphenazine levels between 1 and 3 ng/ml. In one patient, who received an intramuscular dose of fluphenazine decanoate, plasma levels were determined using direct radioimmunoassay, extraction followed by radioimmunoassay and gas liquid chromatography-mass spectrometry. There were good correlation between the three methods.

Administration, Oral↗