Biomedical subjects

G McKay

Publications and source records attributed to G McKay.

At least 19 recordsLinked to original sources

PubMed1992

Synthesis and characterization of quaternary ammonium-linked glucuronide metabolites of drugs with an aliphatic tertiary amine group.

A synthetic approach was developed to make the quaternary ammonium-linked glucuronide metabolites of compounds with an aliphatic tertiary amine group. The key step involved quaternization of the compound with methyl (2,3,4-tri-O-acetyl-alpha-D-glucopyranosyl bromide)uronate and sodium bicarbonate in a two-phase system of water and an organic solvent. The synthetic approach successfully yielded quaternary ammonium-linked glucuronides of 20 drugs and two of their phase I metabolites. The drugs were from various pharmacological classes: H1 antihistamines, antipsychotic agents, and tricyclic antidepressants. Physical data such as HPLC retention times, and diagnostic fast-atom bombardment mass spectra and 1H NMR spectra were obtained. These should aid in the characterization of compounds in samples isolated from biological media.

Amines↗

PubMed1992

Stereoselective pharmacokinetics of doxepin isomers.

Commercial preparations of the tricyclic anti-depressant doxepin contain 15% of the more active cis-doxepin and 85% of the trans-isomer. The single dose pharmacokinetics of doxepin and its major metabolite N-desmethyldoxepin were examined in 30 healthy young men. Results for total doxepin showed wide intersubject variation in all pharmacokinetic parameters except tmax and Cmax. Plasma levels of cis-doxepin were extremely low and it was only possible to estimate the stereoselective pharmacokinetics of the parent drug in 3 subjects. The data from those particular subjects resulted in an average ratio of cis- to trans-doxepin isomers in plasma of 15:85. In contrast, the mean plasma levels of cis-N-desmethyldoxepin in 28 subjects exceeded those of the trans-isomer at every time point after 10 h, such that the areas under the plasma concentration versus time curves (AUC) of cis-N-desmethyldoxepin were significantly higher than those of the corresponding trans-isomer. This phenomenon may play an important role in the therapeutic action of doxepin since it has been suggested that cis-N-desmethyldoxepin is pharmacologically active. In 2 subjects, however, the AUC0-inf of trans-N-desmethyldoxepin were respectively 4 and 8 fold higher than those of the cis-isomer.

Adolescent↗

PubMed1992

The metabolism of piperidine-type phenothiazine antipsychotic agents. I. Sulforidazine in the rat.

1. The metabolism of the piperidine-type, phenothiazine antipsychotic agent, sulforidazine, was studied in female rats after a 20 mg/kg single oral dose. 2. Compounds identified in urine were sulforidazine, sulforidazine ring sulphoxide, the lactam of sulforidazine, the lactam of sulforidazine ring sulphoxide, two diastereomers of N-desmethylsulforidazine ring sulphoxide and a phenolic derivative of sulforidazine. 3. Metabolites were separated by h.p.l.c. prior to mass spectrometric or g.l.c.-mass spectrometric analysis. Except in the case of the phenolic metabolite, structures were confirmed by direct comparison of electron impact mass spectra and chromatographic behaviour with those of authentic samples. To facilitate identification of the phenolic metabolite the crude urinary extract was treated with a silylating reagent and analysed by h.p.l.c.-mass spectrometry with a plasmaspray interface. 4. Despite the availability of authentic standards of sulforidazine N-oxide and sulforidazine N,S-dioxide neither of these compounds could be identified in urinary extracts obtained from rats. 5. Sulforidazine underwent extensive metabolism in rats as only 2.3 +/- 0.4% (n = 5) of the dose was present as unchanged sulforidazine in 24 h urine. The lactam of sulforidazine (0.1 +/- 0.1%) was a minor metabolite whereas the lactam of sulforidazine ring sulphoxide was 3.2 +/- 2.6% dose. 6. Sulforidazine sulphoxide (12.1 +/- 1.6%) was a major metabolite and its diastereomers were present in similar amounts.

Animals↗

PubMed1991

In vitro hydrolysis of RR,SS-threo-methylphenidate by blood esterases--differential and enantioselective interspecies variability.

Enantioselective in vitro hydrolysis of methylphenidate (MPH) by the blood esterases of seven mammalian species is reported. The species included rats, rabbits, dogs, cattle, horses, monkeys, and humans. In vitro incubations up to 8 h were carried out in plasma, red blood cells, and whole blood of the various species. Enantioselective differences were evident among the different species on comparison of the data obtained from the three biological fluids. The esterases present in plasma appeared to show greater activity in the hydrolysis of MPH in all species where comparison with the other two biofluids was possible. Only in the case of humans did esterases present in plasma and red blood cells demonstrate opposite enantioselectivity in the hydrolysis of MPH. Thus after 8 h incubation, the RR-MPH/SS-MPH ratios in plasma and red blood cells were 0.31 and 1.16, respectively.

Animals↗

PubMed1991

Quinidine but not quinine inhibits in man the oxidative metabolic routes of methoxyphenamine which involve debrisoquine 4-hydroxylase.

Healthy male volunteers (n = 13) took a single oral dose of 60.3 mg of methoxyphenamine HCl with and without prior administration of either quinidine (250 mg as bisulphate salt) or its diastereomer quinine (300 mg as sulphate salt). Methoxyphenamine and its N-desmethyl, O-desmethyl and aromatic 5-hydroxy metabolites were quantified in the 0-32 h urine. The oxidative routes of methoxyphenamine metabolisms which had been previously shown to involve debrisoquine 4-hydroxylase, namely O-demethylation and 5-hydroxylation were both significantly inhibited by quinidine in the 12 extensive metabolizers. The inhibition was selective in that N-demethylation which does not involve this isozyme was not affected by quinidine. In all but one of these volunteers the methoxyphenamine/O-desmethylmethoxyphenamine ratio changed such that extensive metabolizers could be classified as poor metabolizers due to quinidine pretreatment. No marked change occurred in the renal excretion of methoxyphenamine and its three metabolites either in the extensive metabolizers because of quinine pretreatment or in the poor metabolizer because of treatment with either quinidine or quinine. Thus in the extensive metabolizer phenotype it was demonstrated in one study that enzyme inhibition of quinidine was selective in terms of the metabolic pathways inhibited as well as stereoselective with respect to the inhibitor.

Adult↗

PubMed1991

Pharmacodynamic effects of buspirone and clobazam.

1. The pharmacodynamic effects of buspirone and clobazam were compared in two volunteer studies. Acute doses of buspirone 5 mg, 10 mg and clobazam 10 mg were contrasted with placebo and a verum (lorazepam 1 mg), in a repeated measures design with 10 subjects assessed on a battery of psychometric tests at 1.5, 3.5, and 5.5 h post dose. For the combined results clobazam and the lower dose of buspirone (5 mg) were significantly contrasted with lorazepam on measures of subjective sedation, memory and choice reaction time (CRT). The higher dose of buspirone was not statistically different from lorazepam for all measures except memory; whilst contrasting significantly with placebo and clobazam on movement and total reaction time components respectively. Though failing to achieve significance, a similar trend was seen for critical flicker fusion (CFF) with buspirone 10 mg and lorazepam producing the lowest scores indicative of increased sedation. 2. Repeated doses of buspirone 5 mg twice daily, clobazam 10 mg twice daily, or placebo twice daily for 8 consecutive days were compared on the same battery of psychometric tests in a repeated measures design. Nine subjects were assessed on days 1, 3, and 8 of the study. Overall, memory performance significantly decreased with buspirone 5 mg in contrast to both clobazam and placebo whilst the opposite trend was seen with CFF. Clobazam significantly improved TRT in contrast to both placebo and buspirone. 3. These results indicate improved reaction time and memory performance with repeated dosing of clobazam in contrast to buspirone. Impairment following acute administration of buspirone appears limited to the higher (10 mg) dose.

Adult↗

PubMed1991

Plasma levels of fluphenazine in patients receiving fluphenazine decanoate. Relationship to clinical response.

The levels of fluphenazine and fluphenazine sulphoxide in schizophrenic patients who were randomly assigned to receive either 5 mg or 25 mg of fluphenazine decanoate every two weeks were monitored. Patients treated with 25 mg of fluphenazine decanoate required three months to reach a steady-state plasma level, indicating that those patients who are being converted from oral to depot fluphenazine should continue to receive oral supplementation during the first three months of treatment with fluphenazine decanoate. Plasma levels of fluphenazine sulphoxide were lower than levels of fluphenazine. At six and nine months following randomisation, there was a statistically significant relationship between lower fluphenazine plasma levels and an increased risk of psychotic exacerbations. A relatively weak relationship was found between fluphenazine plasma levels and akinesia, but non-significant relationships between fluphenazine levels and other neurological side-effects including akathisia, retardation, and tardive dyskinesia. Monitoring the plasma levels may be helpful to clinicians who are attempting to treat stabilised patients with the lowest effective dose of fluphenazine decanoate.

Adult↗

PubMed1991

N(+)-glucuronidation of aliphatic tertiary amines, a general phenomenon in the metabolism of H1-antihistamines in humans.

1. Representative drugs of the various structural classes of H1 antihistamines were chosen for study. The drugs chosen (class name in parentheses) were chlorpheniramine maleate and pheniramine maleate (alkylamines), diphenhydramine hydrochloride and doxylamine succinate (ethanolamines), pyrilamine maleate and tripelennamine hydrochloride (ethylenediamines), promethazine hydrochloride (phenothiazine), cyclizine lactate (piperazine) and terfenadine (miscellaneous). In each case oral dose(s) were administered over no more than 6 h to two healthy volunteers and the total urine collected for 36 h. 2. Metabolites from urine were separated by h.p.l.c. and individually collected prior to mass spectrometric analysis in the fast atom bombardment mode. The structure of each metabolite identified as a quaternary ammonium-linked glucuronide metabolite was confirmed by direct comparison of its mass spectrum and chromatographic behaviour with that of a synthetic authentic compound. 3. For eight of the nine drugs studied, metabolism by the N(+)-glucuronidation pathway was observed in each of the volunteers. Terfenadine was the exception. 4. The amount of each N(+)-glucuronide in the urine was estimated by h.p.l.c. analysis. The mean proportion of dose excreted as the metabolite was 14.3%, 6.5% and 4.0% for cyclizine, tripelennamine and diphenhydramine, respectively. Promethazine was the only case where the N(+)-glucuronide accounted for less than 1.0% of the administered dose in both volunteers examined.

Adult↗

PubMed1991

Quinine is a more potent inhibitor than quinidine in rat of the oxidative metabolic routes of methoxyphenamine which involve debrisoquine 4-hydroxylase.

1. Lewis rats (n = 7 or 8) were dosed with methoxyphenamine with and without prior administration of various doses of either quinine or its diastereomer quinidine. Methoxyphenamine and its N-desmethyl, O-desmethyl and aromatic 5-hydroxy metabolites were quantified in 0-24 h urine. 2. The oxidative routes of methoxyphenamine metabolism which had been previously shown to involve the debrisoquine/sparteine isoenzyme, namely O-demethylation and 5-hydroxylation, were both significantly inhibited by quinine. The inhibition was selective in that N-demethylation which does not involve this isoenzyme was not affected by quinine. 3. Quinidine which had been previously shown at a relatively high dose (80 mg/kg) to affect the three metabolic routes of methoxyphenamine in a similar fashion was ineffective in this regard at a 25 mg/kg dose. Quinine more effectively inhibited the O-demethylation and 5-hydroxylation of methoxyphenamine than did quinidine, and its inhibition was marked at the lowest dose examined, 12.5 mg/kg. 4. As quinidine is a more potent inhibitor than quinine of debrisoquine 4-hydroxylase in man, the rat should be used only with full realization of its limitations when investigating substrates metabolized by this isoenzyme.

Animals↗

PubMed1991

The metabolites of chlorpromazine N-oxide in rat bile.

1. The metabolism of chlorpromazine N-oxide was studied in female rats after a 20 mg/kg single i.p. dose. 2. Metabolites identified in urine and faeces were chlorpromazine, 7-hydroxychlorpromazine, chlorpromazine sulphoxide, N-desmethylchlorpromazine and N-desmethylchlorpromazine sulphoxide. As these same five metabolites were previously shown to be present after oral administration this indicates that reduction of chlorpromazine N-oxide occurs not only in the gastrointestinal tract but also at other sites. 3. The metabolism of chlorpromazine N-oxide was studied following its administration by either i.p., i.v. or oral routes to female rats in which the bile duct was cannulated. 4. There were no qualitative differences between the three routes of administration with respect to the metabolites identified. With the exception of the absence of N-desmethylchlorpromazine and N-desmethylchlorpromazine sulphoxide, all metabolites previously identified in urine and faeces were also present in bile. 5. Additionally there were three compounds present in rat bile which were not identified in urine or faeces. These were chlorpromazine N-oxide, chlorpromazine N,S-dioxide and 7-hydroxychlorpromazine O-glucuronide. This is the first unequivocal evidence for the identification of intact 7-hydroxychlorpromazine O-glucuronide in any species. 6. The inability to detect chlorpromazine N-oxide and chlorpromazine N,S-dioxide in the faeces of rats is likely to be due to the reduction of the N-oxide group on the passage of these biliary metabolites down the intestinal tract.

Animals↗

PubMed1990

Comparative bioavailability of two tablet formulations of fluphenazine dihydrochloride in drug-free psychiatric patients.

The comparative bioavailability of a new tablet formulation of fluphenazine dihydrochloride (5 mg) and a reference product (fluphenazine dihydrochloride, Prolixin, 5 mg) was assessed in drug-free psychiatric patients. Twenty-six patients were initially entered in the study, of whom 22 completed the protocol. Each patient received the test (T) and the reference formulation (R) in a balanced two-way crossover design. Plasma concentrations of fluphenazine were monitored over a period of 48 h after drug administration using a sensitive HPLC method. One patient did not show any measurable plasma concentration for one formulation at any sampling time and, therefore, bioavailability was assessed in the remaining 21 patients. All pharmacokinetic parameters showed wide intersubject variation. The maximum plasma concentration (Cmax), time to Cmax, and area under the curve up to the last measurable concentration (AUClast0), infinity (AUCinfinity0), or truncated areas (such as AUC16(0), AUC24(0) were compared by analyses of variance and found not to be significantly different in each case across the formulations. Except for AUC24(0), AUC32(0), and AUC48(0), ANOVA of all other parameters showed a high power (greater than 80%) to detect a 20% difference in the mean value of each bioequivalence parameter between T and R. The two formulations were found to be bioequivalent in that confidence intervals of the mean values of AUCinfinity0, AUClast0, truncated AUCs, or Cmax for T:R ratios were, in each case, well within the acceptable range of 100 +/- 20%.

Biological Availability↗

PubMed1990

Bioequivalence of two thorazine tablet formulations using radioimmunoassay and gas chromatographic-mass spectrometric methods.

Two analytical methods for the analysis of chlorpromazine (CPZ), a radioimmunoassay (RIA) and a GLC-MS method, were compared in a bioequivalence study of two CPZ tablet formulations (Thorazine: film coated and sugar coated). Thirty-six nonsmoking, healthy, male volunteers completed the study. Each subject ingested single doses (2 x 25 mg) of the test (T) and the reference (R) formulations in a two-way crossover design with a two-week drug-free interval between doses. Following each administration, plasma concentrations of CPZ were monitored over a period of 24 h by both RIA and GLC-MS methods. Plasma concentrations and pharmacokinetic parameters determined by either analytical method showed wide intersubject variation, with the GLC-MS data showing relatively higher magnitude of intersubject variation than the RIA data. In general, plasma concentrations measured by RIA were significantly different from those measured by GLC-MS (paired t tests: p less than 0.0001). As indicated by the regression analysis, concentrations determined by RIA were 1.3-1.4 times higher than those determined by GLC-MS. There were strong and significant correlations between the two methods for both T and R (r greater than 0.75: p less than 0.0001). Similar statistical relationships were found between the plasma concentrations of CPZ determined by the two methods at each sampling time and the bioequivalence parameters area under the plasma level versus time curves up to the last measurable concentration (AUCt0) and the maximum plasma concentration (Cmax).(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

PubMed1990

Development and application of a radioimmunoassay for fluphenazine based on monoclonal antibodies and its comparison with alternate assay methods.

The development of a monoclonal antibody towards fluphenazine allows the measurement of plasma concentrations of this highly potent neuroleptic. The method demonstrates sufficient sensitivity to measure 0.02 ng of fluphenazine per milliliter of plasma and employs a 150-microL plasma extract derived from a 2-mL plasma sample. The procedure is linear over the concentration range of 0.02 to 2.5 ng/mL, with a mean overall coefficient of variation of less than 3%. The validity of the described monoclonal-based RIA procedure was confirmed by comparison to alternate assay methods in replicate samples. Comparison to a newly developed HPLC-coulometric procedure in 159 samples showed a strong correlation, with a slope value of close to unity (1.0484) and a coefficient of correlation of 0.8136, while comparison to a previously developed polyclonal-based RIA procedure showed a correlation of 0.95 and a slope of 0.91 (n = 26).

Animals↗

PubMed1990

Therapeutic monitoring of steady-state plasma levels of the N4'-oxide metabolite of fluphenazine in chronically treated schizophrenic patients determined by a specific and sensitive radioimmunoassay.

Highly specific and sensitive antisera for fluphenazine-N4'-oxide (FLUNO) were obtained from New Zealand white rabbits immunized with a bovine serum albumin conjugate of 7-(3-carboxypropionyl)propchlorperazine-N4'-oxide. One of the antisera was used to develop a radioimmunoassay (RIA) procedure that enabled for the first time the determination of steady-state plasma levels of FLUNO, an active metabolite, in patients treated with oral or intramuscular (i.m.) fluphenazine (FLU). This method has sufficient sensitivity to quantitate accurately 20 pg of FLUNO in 200 microliters of plasma extract with a coefficient of variation of less than 8%. The antiserum had negligible cross-reactivity (less than 2%) with FLU and its major metabolites such as FLU sulfoxide, 7-hydroxy-FLU, and N-deshydroxyethyl-FLU. To confirm that the developed RIA procedure specifically quantitated FLUNO, FLUNO was selectively reduced to FLU by sodium dithionite in plasma samples from patients. A good correlation (r2 = 0.9646) was observed between the total FLU level and the sum of FLU and FLU equivalent to FLUNO determined separately in the same plasma. The steady-state plasma concentrations of FLUNO in patients receiving a daily oral dose of 5 to 20 mg of FLU dihydrochloride ranged from 13 to 378% of that of FLU, whereas this value ranged from 10 to 214% in plasma samples from patients treated with a biweekly intramuscular (i.m.) dose of 5 mg of FLU decanoate.

Administration, Oral↗

PubMed1990

The metabolism of chlorpromazine N-oxide in man and dog.

1. The metabolism of chlorpromazine N-oxide was studied in female dogs and adult male humans after a single oral dose. 2. There was extensive metabolism in both species in that between four and seven metabolites were separately identified in urine and faeces. Apart from chlorpromazine N-oxide, chlorpromazine N,S-dioxide was the only isolated metabolite which retained the N-oxide group. The other identified metabolites were chlorpromazine and its 7-hydroxy, sulphoxide, N-desmethyl, 7-hydroxy-N-desmethyl and N-desmethylsulphoxide derivatives. 3. With dog samples, metabolites were separated by h.p.l.c. and individually collected prior to mass spectrometric analysis. With human samples, metabolites were directly subjected to h.p.l.c.-mass spectrometric determination. With all metabolites their structures were confirmed by direct comparison of their mass spectra and chromatographic behaviours with those of authentic samples. 4. The metabolites identified in urine and faeces were for the most part the same in both species, with the exceptions that chlorpromazine N-oxide was identified in the faeces of dog only and 7-hydroxy-N-desmethylchlorpromazine was identified in the urine of man only. 5. The observation of N-oxide compounds in the excreta of both man and dog contrasted with that for the previously studied rat, where no such compounds were detected.

Animals↗

PubMed1990

Fluphenazine plasma levels and clinical response.

We monitored fluphenazine plasma levels in 39 schizophrenic patients who participated in a 2-year double-blind comparison of 5 mg and 25 mg of fluphenazine decanoate (FD) administered every 14 days. We investigated the relationship between log-transformed plasma levels at 3, 6, and 9 months and subsequent psychotic exacerbations with logistic regression and survival analysis. Using logistic regression, the relationship was nonsignificant at 3 months (chi-square = .21, df = 1, p = .65), but significant at 6 months (chi-square = 4.38, df = 1, p = .04) and 9 months (chi-square = 8.98, df = 1, p = .003). Using survival analysis with fluphenazine levels as a covariate (Cox models), we also found significant relationships between the fluphenazine plasma level and the risk of exacerbations at 6 months (chi-square = 3.77, df = 1, p = .052) and 9 months (chi-square = 12.21, df = 1, p = .0005), but not at three months (chi-square = 0.87, df = 1, p = .65). These findings suggest that the measurement of fluphenazine plasma levels may be helpful in decision-making about the dosage of FD.

Adult↗

PubMed1989

Enantioselective gas chromatographic assays with electron-capture detection for methoxyphenamine and its three primary metabolites in human urine.

Sensitive and enantioselective gas chromatographic assays have been developed and applied to the quantitation in human urine of the enantiomers of methoxyphenamine and its three primary oxidative metabolites, namely, N-desmethylmethoxyphenamine, O-desmethylmethoxyphenamine and 5-hydroxymethoxyphenamine. The separation of the various analytes was achieved through the combined use of high-resolution gas chromatography coupled with electron-capture detection and employing a capillary OV-225 column. The formation of diastereometric derivatives involved the chiral acylating reagent N-heptafluorobutyryl-L-prolyl chloride. The assays for methoxyphenamine and O-desmethylmethoxyphenamine were linear over the range 0.25-2.0 micrograms/ml for each analytes' enantiomers, while in the case of the enantiomers for N-desmethylmethoxyphenamine and 5-hydroxymethoxyphenamine linearity was shown over the ranges 0.094-0.75 and 0.188-1.5 micrograms/ml, respectively. The mean coefficients of variation in all cases were less than 4%.

Amphetamines↗

PubMed1989

Comparative bioavailability of a new commercial tablet formulation and two lots of a reference formulation of haloperidol.

The bioavailability of a new tablet formulation (5 mg) of haloperidol was estimated relative to two lots of a reference product. Twenty-eight healthy male volunteers completed all three phases in that they received the test (T) and the two reference formulations (R1 and R2) in a balanced three-way crossover design. Using a sensitive HPLC method, plasma concentrations of haloperidol and reduced haloperidol were monitored over a period of 96 h following administration of each formulation. Haloperidol was measurable in the plasma of all the volunteers, whereas reduced haloperidol was measurable in only 6 out of 28 volunteers following each administration. Therefore, the assessment of bioequivalence in this study is based on haloperidol data only. The maximum plasma concentration (Cmax), time to Cmax (tmax), and area under the curve up to the last measurable concentration (AUCot) or infinity (AUCo infinity) were compared by analyses of variance and found not to be significantly different across the formulations. The relative bioavailability based on T:R1 or T:R2 ratios of AUCo infinity, AUCot, and Cmax was, in each case, within the acceptable range of 100 +/- 20%. Also, the relative bioavailability of R1 compared with R2 was within 100 +/- 20% in terms of the above bioavailability parameters. Except for tmax, all other pharmacokinetic parameters showed wide intersubject variation.

Adolescent↗