Cimetidine-doxepin interaction.
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Cimetidine↗
Biomedical subjects
G McKay
Publications and source records attributed to G McKay.
Methoxyphenamine and dextromethorphan as safe probes for debrisoquine hydroxylation polymorphism.
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Debrisoquin↗
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↗
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↗
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↗
Subnanogram quantitation of chlorpheniramine in plasma by a new radioimmunoassay and comparison with a liquid chromatographic method.
A new radioimmunoassay (RIA) procedure for the quantitation of chlorpheniramine in plasma is described. The assay allows the determination of chlorpheniramine levels up to 96 h after oral administration of a single 4-mg tablet to healthy volunteers. This procedure was sensitive to a 156-pg/mL plasma concentration when a 100-microL plasma sample was used. The mean coefficient of variation over the linear range of the assay from 0.156 to 20 ng/mL was 3.79%. The specificity of the assay was investigated, and the antisera showed 7% cross-reactivity with the N,N-didemethyl analogue and 17% cross-reactivity with the N-demethyl analogue. This high degree of specificity was also evident from the findings that the plasma concentrations determined by this newly described RIA procedure in samples of two healthy male volunteers who were administered 4 mg of chlorpheniramine maleate orally gave a strong correlation (r2 = 0.88) with values obtained by an HPLC-UV procedure. The antiserum cross-reacted 100% with brompheniramine and, thus, can be used for its analysis in plasma. The described RIA procedure is precise, simple, and capable of handling a large number of plasma samples with a minimal turnaround time.
Blood Specimen Collection↗
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↗
The effect of sample storage on the stability of chlorpromazine in plasma and whole blood.
The stability of chlorpromazine in heparinized whole blood and plasma was investigated at three different concentrations (5, 20, and 50 ng/ml) after storage at -20 degrees C for 0, 7, 14, 28, 56, and 84 days. A statistical analysis was done to determine whether there was any significant difference between the concentration of chlorpromazine in these body fluids as determined on day one versus each of the later dates of analysis. The results indicate that no significant difference was found over the course of these investigations.
Chlorpromazine↗
Plasma concentrations of trifluoperazine following single low doses.
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Chromatography, Gas↗
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↗
Subnanogram quantitation of chlorpromazine in plasma by high-performance liquid chromatography with electrochemical detection.
A specific and sensitive high-performance liquid chromatographic (HPLC) method for the quantitative determination of subnanogram levels of chlorpromazine in plasma is described. Following extraction of chlorpromazine and the internal standard, prochlorperazine, HPLC analysis is carried out on a cyano column with a mobile phase consisting of 0.1 M ammonium acetate in acetonitrile (10:90 v/v). The use of oxidative thin-layer amperometric detection allowed the quantitation of 0.25 ng of chlorpromazine/ml of plasma with a coefficient of variation of 5.1%. The HPLC method has adequate sensitivity to follow plasma concentration-time profiles up to 24 hr following low single oral doses of chlorpromazine in healthy volunteers.
Chlorpromazine↗
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↗
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↗
Recent advances in the analysis of phenothiazine drugs and their metabolites using high performance liquid chromatography.
HPLC procedures with electrochemical or ultraviolet detection were developed in order to analyze plasma samples from patients and volunteers who had received antipsychotic drugs. Procedures were described for the determination of chlorpromazine and trimeprazine in human plasma. The described procedures for chlorpromazine and trimeprazine demonstrated sufficient sensitivity for their use in pharmacokinetic studies following low single oral doses of these agents. The HPLC-EC procedures for chlorpromazine and trimeprazine were compared with GC-MS and radioimmunoassay procedures, respectively.
Adult↗
Radioimmunoassay for prochlorperazine in human plasma.
A new sensitive, specific, and rapid radioimmunoassay procedure for the determination of plasma concentrations of the antiemetic drug prochlorperazine is described. The assay enables the quantitation of 31 pg of the drug in 200 microliters of plasma with a coefficient of variation of approximately 2%. Except for N-desmethylprochlorperazine, the antiserum did not cross-react with the available metabolites tested. Also there was no cross-reactivity with the tricyclic antidepressants and antianxiety agents commonly co-administered with the drug. The method is suitable for single-dose pharmacokinetic and bioavailability studies. It should be adequate for the therapeutic monitoring of the drug in patients.
Animals↗
Kinetics of oral trifluoperazine disposition in man.
The disposition of trifluoperazine (TFP) was studied in five healthy volunteers following oral administration of a 5 mg tablet. Using a very sensitive GC-MS technique plasma TFP concentrations were measured up until 24 h following drug ingestion. Peak plasma concentrations varied widely (range 0.53-3.09 ng ml-1) and were reached 2.8 +/- 0.5 h following ingestion of the TFP tablet. The apparent terminal elimination half-life of TFP was 12.5 +/- 1.4 h. The area under the plasma concentration-time curve differed widely between subjects (range: 5.9-17.6 ng ml-1 h) suggesting large individual differences in the extent of presystemic TFP elimination.
Administration, Oral↗
Identification of new secondary metabolites of methoxyphenamine in man.
Metabolites of methoxyphenamine were examined in the urine of three healthy human volunteers. The metabolites were separated by g.l.c. and identified by comparison of their chromatographic and mass-spectrometric behaviours with those of authentic synthetic compounds. 5-Hydroxy-2-methoxy-N-methylamphetamine, a metabolite previously identified by indirect methods, was conclusively identified by comparison with the now-available authentic synthetic material. In addition, three new metabolites of methoxyphenamine were identified--5-hydroxy-2-methoxyamphetamine, 2-methoxyphenylacetone and 5-hydroxy-2-methoxyphenylacetone.
Chromatography, Gas↗
High-performance liquid chromatographic assay of indomethacin and its application in pharmacokinetics in healthy volunteers.
A new sensitive high-performance liquid chromatographic method for indomethacin from plasma on a reversed-phase column (C18) has been developed. The method involves precipitation of plasma with perchloric acid followed by diethyl ether extraction. The assay is quantitative down to 0.25 microgram ml-1 from a 200-microliters aliquot of plasma with a detection limit of 0.1 microgram ml-1 and a recovery of approximately 90%. The method was applied to single-dose studies with volunteers under various dietary restrictions. The results of these studies indicated that intrasubject variability within these regimens may be as important a factor as the intersubject variability already documented for this drug. These results have important implications in the determination of bioavailability and pharmacokinetic parameters of this drug.
Chromatography, High Pressure Liquid↗