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At least 19 recordsLinked to original sources
PubMed1987

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↗
PubMedDate not supplied

Methoxyphenamine inhibits histamine-induced bronchoconstriction in anaesthetized guinea-pigs and histamine-induced contractions of guinea-pig ileum in vitro.

Measurements were made of the effects of methoxyphenamine hydrochloride on histamine-, acetylcholine- and U46619-induced bronchoconstriction in pentobarbitone-anaesthetized guinea-pigs, and on histamine- and acetylcholine-induced contractions of guinea-pig ileum in vitro. Methoxyphenamine (20 mg/kg, i.v.) did not affect bronchoconstriction induced by acetylcholine or the thromboxane A2-mimetic U46619. However, it produced a parallel rightward shift [2.94-(1.79, 4.41) fold, 95% confidence limits in parentheses] of the curve relating bronchoconstrictor responses to log-dose of histamine at a total dose of 13 mg/kg, i.v., which was not significantly different from the shift [3.30-(1.93, 5.56) fold] produced by 3 micrograms/kg, i.v., of the histamine antagonist mepyramine maleate. Histamine-induced contractions of the isolated guinea-pig ileum were antagonized by methoxyphenamine (10(-5) to 10(-3) M). The histamine log-concentration-response curve was shifted to the right in a parallel manner by methoxyphenamine (10(-5) to 10(-4) M), without depression of maximum responses. However, at higher concentrations, maximum responses were reduced. The slope of the Schild plot was significantly different from -1. The degree of the rightward shift of the concentration-response curves to histamine, produced by 10(-5) M of methoxyphenamine [3.90-(2.83, 4.97) fold], was not significantly different from that produced by 3 x 10(-9) M of mepyramine [4.60-(2.86, 6.52) fold]. Methoxyphenamine, at concentrations of 10(-5) to 3 x 10(-4) M, had no significant effect on responses of guinea-pig ilea to acetylcholine (10(-9) to 10(-5) M). These results indicate that methoxyphenamine antagonizes the effects of histamine both in vivo and in vitro. In vitro studies indicate a noncompetitive antagonism.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
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↗
PubMed1990

Methoxyphenamine inhibits basal and histamine-induced nasal congestion in anaesthetized rats.

1. Nasal resistance in anaesthetized rats was assessed by measuring air overflow during ventilation of the nasal passages at constant pressure. Nasal basal resistance was reduced in a dose-dependent manner by methoxyphenamine hydrochloride (0.01-30 mg kg-1, i.v.), pseudoephedrine hydrochloride (0.03-3 mg kg-1, i.v.) and adrenaline bitartrate (0.01-3 micrograms kg-1, i.v.). Both methoxyphenamine and pseudoephedrine were less potent and less efficacious than adrenaline but caused longer-lasting responses. 2. Nasal congestion induced by histamine (0.2% nebulised solution passed into the nasal passages for 15 s) was inhibited by i.v. administration of methoxyphenamine, pseudoephedrine, adrenaline, methoxamine or tyramine: the ID50s against 0.2% histamine-induced nasal congestion were 1.16 (95% confidence limits; 0.5, 1.8) mg kg-1, 0.25 (0.19, 0.33) mg kg-1, 0.037 (0.018, 0.06) micrograms kg-1, 8.12 (6.74, 9.65) micrograms kg-1 and 30.6 (26.1, 35.8) micrograms kg-1 respectively. 3. The inhibitory effects of both methoxyphenamine and tyramine on histamine-induced nasal congestion were reduced after administration of desmethylimipramine (0.1 and 1 mg kg-1, i.v.) or prazosin (0.1 and 0.3 mg kg-1, i.v.). Similarly, the inhibitory effects of methoxamine were reduced after prazosin (0.1 and 0.3 mg kg-1). 4. These results indicate that methoxyphenamine (1 mg kg-1, i.v.) inhibits histamine-induced nasal congestion in the rat. This action, at least in part, is probably indirect being mediated by release of neuronal noradrenaline which then acts on alpha 1-adrenoceptors.

Airway Resistance↗
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↗
PubMed1989

Selective in vivo inhibition by quinidine of methoxyphenamine oxidation in rat models of human debrisoquine polymorphism.

1. Lewis and Dark Agouti (DA) rat strains (n = 4), models of human extensive and poor metabolizer phenotypes of debrisoquine/sparteine, respectively, were dosed with methoxyphenamine with and without prior administration of quinidine. Methoxyphenamine and its three metabolites, namely N-desmethylmethoxyphenamine, O-desmethylmethoxyphenamine and 5-hydroxymethoxyphenamine were quantified in 0-24 h urine. 2. The oxidative metabolic routes of methoxyphenamine which had been previously shown to involve the debrisoquine/sparteine isozyme, namely O-demethylation and aromatic 5-hydroxylation, were both significantly inhibited by quinidine in the two rat strains. 3. The oxidative metabolic route of methoxyphenamine which had been previously shown to not involve the debrisoquine/sparteine isozyme, namely N-demethylation, was not significantly inhibited by quinidine in either rat strain. 4. The Lewis strain pretreated with quinidine resembled the DA strain without such pretreatment in terms of O-desmethylmethoxyphenamine and 5-hydroxymethoxyphenamine in that the mean percentages of the dose excreted as these two metabolites and the mean O-desmethylmethoxyphenamine/methoxyphenamine and 5-hydroxymethoxyphenamine/methoxyphenamine ratios were similar to one another. 5. Ten days after quinidine administration to the Lewis strain of rat, all parameters of methoxyphenamine and its metabolites returned to normal. 6. A protocol involving substrate administration to Lewis strain rats with and without prior administration of quinidine could be developed as an attractive approach to screen substrates for metabolism in vivo by the debrisoquine/sparteine isozyme. Such an approach obviates interstrain differences.

Amphetamines↗
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

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↗
PubMed2003

HPLC determination of aminophylline, methoxyphenamine hydrochloride, noscapine and chlorphenamine maleate in compound dosage forms with an aqueous-organic mobile phase.

A high-performance liquid chromatography procedure for the simultaneous determination of aminophylline, methoxyphenamine hydrochloride, noscapine and chlorphenamine maleate in commercially available compound capsule dosage forms has been developed and validated. The separation and quantification were achieved on an Ultrasphere C18 column using a mobile phase of dichloromethane-methanol-0.25% (v/v) diethylamine aqueous solution (20:60:20, v/v/v) at a flow rate of 1 ml min(-1) with detection of all analytes at 264 nm. The separation was achieved within 6 min for each drug mixture. The method showed good linearity for the aminophylline, noscapine, chlorphenamine maleate and methoxyphenamine hydrochloride mixture in the 125-750, 35-210, 10-60 and 62.5-375 microg ml(-1) ranges, respectively. The intra- and inter-day R.S.D.s ranged from 0.4 to 0.5%, 0.4-0.6%, 0.5-0.7% and 0.4-0.6% for aminophylline, noscapine, chlorphenamine maleate and methoxyphenamine hydrochloride, respectively. The recoveries (mean+/-S.D.) of low, middle and high concentrations were 99.9+/-0.9, 100.4+/-1.3 and 99.7+/-0.7% for aminophylline; 99.9+/-1.1, 100.4+/-0.7 and 100.1+/-0.8% for noscapine; 99.8+/-1.1, 99.7+/-1.0 and 100.7+/-0.8% for chlorphenamine maleate; and 99.8+/-0.9, 100.4+/-1.6 and 99.9+/-0.9% for methoxyphenamine hydrochloride, respectively.

Adrenergic beta-Agonists↗
PubMed1989

Effect of sparteine and quinidine on the metabolism of methoxyphenamine by Cunninghamella bainieri.

1. The fungus C. bainieri, incubated for 7 days with methoxyphenamine alone or in combination with either sparteine or quinidine, gave N-desmethylmethoxyphenamine and its N-acetyl conjugate as major metabolites, while O-desmethylmethoxyphenamine, 5-hydroxymethoxyphenamine and 2-hydroxyamphetamine were produced in lesser amounts. In addition, 1-(2-hydroxyphenyl)-2-aminopropane, 1-hydroxy-1-(2-methoxyphenyl)-2-propanone, beta-hydroxymethoxyphenamine, and 1-(5-hydroxy-2-methoxyphenyl)-2-aminopropane were tentatively identified as minor components of the fungal biotransformation of methoxyphenamine. 2. As observed in mammalian systems, the addition of either sparteine or quinidine decreased the rate and extent of methoxyphenamine biotransformation. 3. C. bainieri may be a useful model for drug interaction studies.

Biotransformation↗
PubMed1990

Kinetics of in vitro metabolism of methoxyphenamine in rats.

1. Methoxyphenamine (MP) was metabolized in vitro by rat liver preparations to O-desmethylmethoxyphenamine (O-desmethyl-MP), N-desmethylmethoxyphenamine (N-desmethyl-MP) and 5-hydroxymethoxyphenamine (5-hydroxy-MP). These metabolic pathways were inhibited by SKF 525-A and carbon monoxide, which indicates that these reactions were mediated at least partly by an NADPH-dependent cytochrome P-450 system. 2. Strain differences in the metabolism of this drug in vitro were observed in female Lewis and Dark Agouti (DA) rats, which are proposed models for human debrisoquine phenotypes. Methoxyphenamine O-demethylase and 5-hydroxylase activity in DA rats were lower than those in Lewis rats. 3. The metabolic transformation of methoxyphenamine in vitro to O-desmethyl-MP was inhibited competitively by debrisoquine and sparteine. This indicates that the cytochrome P-450 isoenzyme mediating the metabolism of MP to O-desmethyl-MP is similar to that mediating metabolism of debrisoquine and sparteine. However, no inhibition was observed with methenytoin.

Animals↗
PubMed1987

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↗
PubMed1978

Excretion of methoxyphenamine and its metabolites in rat urine.

Metabolites of methoxyphenamine in urine obtained after oral administration of the drug to rats have been isolated by Sephadex LH-20 column chromatography and identified as the O-, N,O- and N-demethylated derivatives of methoxyphenamine by thin-layer chromatography, spectrometry, and comparisons with synthesized compounds. The unchanged drug and the metabolites excreted in urine have been extracted and determined by gas chromatography after treatment with trifluoroacetic anhydride.

Administration, Oral↗
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↗
PubMedDate not supplied

Hair analysis for drugs of abuse. III. Movement and stability of methoxyphenamine (as a model compound of methamphetamine) along hair shaft with hair growth.

This paper describes the movement of methoxyphenamine (MOP, a model compound of methamphetamine) along the hair shaft at the rate of hair growth and the stability of drugs in hair for several months. Five healthy subjects (3 males and 2 females) took 50 mg of methoxyphenamine orally once a day for 7 days. Scalp hairs from the posterior vertex were collected every 2 weeks or every 8 weeks after the first dosage. The hairs were cut into 1-cm sections and extracted with methanol-5N HCl (20:1). MOP in the extract was determined by gas chromatography/mass spectrometry (GC/MS) with tetradeuterium labeled MOP as an internal standard. The drug moved along hair shaft at the rate of 2.8-3.2 mm/week, according to hair growth, without diffusion. When drug bands were extrapolated according to the sections in which drug was detected, the bands were approximately 5 mm wide, equivalent to 1.7-2.4 periods of 7-day hair growth. In the case of identical doses, the drug level was highest in the root side and lowest in the distal side. In our data, we found that the drug level in hair had decreased approximately 50% five months later. The ratio of drug levels in corresponding sections correlated well to the ratio of doses, except where the hair shafts had been damaged or the drugs had decomposed.

Adult↗
PubMed1983

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↗
PubMed1995

Metabolism of methoxyphenamine and 2-methoxyamphetamine in P4502D6-transfected cells and cell preparations.

1. Control and P4502D6-transfected human B-lymphoblastoid cell lines (cHol and h2D6v2 respectively) were used to study 2D6-mediated metabolism of methoxyphenamine (MPA) and 2-methoxyamphetamine (2MA). The main metabolites were products of O-dealkylation and aromatic hydroxylation at the 5-position. In addition, N-desmethyl-methoxyphenamine (NDMP) was also identified as a minor metabolite of MPA in extracts of these cells, confirming previous reports of 2D6-mediated N-demethylation of MPA. 2. An additional ring-hydroxylated metabolite of MPA and 2MA has been tentatively identified as the corresponding 3-hydroxy-2-methoxy derivative. 3. MPA metabolism in whole cells was time dependent, with approximately 30% of the MPA metabolized after 72 h. A 35% conversion of MPA was achieved on average with cell lysates. Only 18% 2MA was metabolized. By contrast, control cells (cHol) showed no evidence of any MPA or 2MA metabolites even after 96-h incubation. 4. Continuous presence of haemin/dimethylsulphoxide (DMSO) throughout the 4-day incubation with MPA resulted in a shift in the metabolite profile towards the production of NDMP at the expense of the other products. 5. In summary, h2D6v2 cells, lysates and microsomes can form all metabolites of MPA and can be used in drug interaction studies.

Amphetamines↗
PubMed1995

The influence of pregnancy on the biotransformation and urinary excretion of methoxyphenamine in mice.

(i) The urinary elimination of methoxyphenamine (MPA) and its metabolites in underivatized samples was examined after single and multiple oral administration to pregnant and non-pregnant mice by GLC and GLC-MS. (ii) The major metabolite O-desmethylmethoxyphenamine (ODMP), along with lesser amounts of N-desmethylmethoxyphenamine (NDMP) and 2-hydroxyamphetamine (2OH), were the only metabolites detected in urine extracts of pregnant and non-pregnant mice. 5-Hydroxymethoxyphenamine (5HMP) was not detected. Enzyme hydrolysis did not increase the recovery of either substrate or metabolites in either the pregnant or non-pregnant animals. The results show that MPA metabolism in the Swiss-Webster mouse is distinctly different from that seen in man and other laboratory animals. (iii) The mean MPA:ODMP ratio in day-6 urine from pregnant mice after a single dose was 0.31 +/- 0.04. The NDMP:ODMP ratios were less than 0.10 in all samples. Non-pregnant mice urine had equivalent amounts of MPA, NDMP, ODMP, and 2OH after multiple dosing. (iv) While multiple dosing and pregnancy did not alter either the urinary recovery or profile of the metabolites detected, there was a linear decrease in the MPA:ODMP ratio during gestation. (v) MPA was extensively metabolized to ODMP in the male mice, and the MPA:ODMP ratio of 0.41 was slightly higher than that observed in the pregnant and non-pregnant females.

Animals↗