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H C Thompson

Publications and source records attributed to H C Thompson.

At least 73 records · Page 4Linked to original sources

Metabolism of doxylamine succinate in Fischer 344 rats. Part I: Distribution and excretion.

Experiments were conducted with male and female rats (12 per group) dosed by gavage with 2 or 20 mg (based on the free amine) doxylamine succinate containing about 10 microCi 14C-doxylamine succinate to determine distribution and excretion of the activity as a function of dose and sex with time. Urine and feces were collected at intervals up to 72 hr. Most of the dose (approximately equal to 70%) was eliminated in the first 24 hr after dosing and 95 to 100% of the dose was recovered during the 72-hr course of the experiments with both sexes and dose levels. Less than 1% of the total dose remained in the rats at the end of the test period. The urinary route of elimination was more predominant than the fecal route in both sexes given the 20-mg dose. The fecal route predominates in low-dose males whereas there is no significant difference between urinary and fecal routes of elimination in low-dose females. Preliminary characterization of urinary metabolite form using extraction techniques shows 99% of the metabolites to be in the polar conjugated form.

Animals↗

Metabolism of 14C-labeled doxylamine succinate (Bendectin) in the rhesus monkey (Macaca mulatta).

The time-course of the metabolic fate of [14C]doxylamine was determined after the p.o. administration of 13 mg/kg doxylamine succinate as Bendectin plus [14C]doxylamine succinate to the rhesus monkey. Urine and plasma samples were analyzed by reversed-phase high performance liquid chromatography (HPLC), chemical derivatization, and mass spectrometry. The cumulative 48-hr urinary metabolic profile contained 81% of the administered radiolabeled dose and consisted of at least six radiolabeled peaks. They were peak 1: unknown polar metabolites (8% of dose); peak 2: 2-[1-phenyl-1-(2-pyridinyl)ethoxy] acetic acid, 1-[1-phenyl-1(2-pyridinyl)ethoxy] methanol, and another minor metabolite(s) (31%); peak 3: doxylamine-N-oxide (1%); peak 4a: N,N-didesmethyldoxylamine (17%); peak 4b: doxylamine (4%); and peak 5: N-desmethyldoxylamine (20%). The plasma metabolic profile was the same as the urinary profile except for the absence of doxylamine-N-oxide. The maximum plasma concentrations and elapsed time to attain these concentrations were as follows. Peak 1: 540 ng/mL, 4 hr; peak 2: 1700 ng/mL, 1 hr; peak 4a: 430 ng/mL, 4 hr; peak 4b: 930 ng/mL, 2 hr; and peak 5: 790 ng/mL, 2 hr. These data suggest that in the monkey, doxylamine metabolism follows at least four pathways: a minor pathway to the N-oxide; a minor pathway to unknown polar metabolites; a major pathway to mono- and didesmethyldoxylamine via successive N-demethylation; and a major pathway to side-chain cleavage products (peak 2) via direct side-chain oxidation and/or deamination.

Animals↗

Identification of pyrilamine metabolites by ammonia chemical ionization mass spectrometry.

The ammonia chemical ionization mass spectrometric analysis of pyrilamine, the N-oxide of pyrilamine, and related compounds is described. The use of ammonia as the reagent gas produced excellent [M + H]+ ions for these compounds. The suitability of this method for the analysis of two rat urinary metabolites of pyrilamine is demonstrated.

Aminopyridines↗

Metabolism of doxylamine succinate in Fischer 344 rats. Part II: Nonconjugated urinary and fecal metabolites.

Elimination and metabolic profiles of doxylamine and its nonconjugated metabolites were determined after the oral administration of [14C]-doxylamine succinate (13.3 mg/kg and 133 mg/kg doses) to male and female Fischer 344 rats. Total urine and fecal recovery of the administered dose was greater than 90% regardless of sex or dose. The cumulative urinary and fecal elimination of these nonconjugated doxylamine metabolites at the 13.3 mg dose was 44.4 +/- 4.4% and 36.0 +/- 5.8% of the total recovered dose for male and female rats, respectively. The cumulative urinary and fecal elimination of the doxylamine nonconjugated metabolites at the 133 mg/kg dose was 38.7 +/- 2.7% and 41.4 +/- 1.0% of the total recovered dose for male and female rats, respectively. In order to determine the contribution of mammalian and bacterial enzymes in the overall metabolism and excretion patterns for doxylamine, two in vitro techniques were investigated. Incubation of [14C]-doxylamine succinate with human and rat intestinal microflora indicated that anaerobic bacteria were not capable of effecting the degradation of [14C]-doxylamine succinate. However, the incubation of [14C]-doxylamine succinate with isolated rat hepatocytes generated several metabolites similar to those observed in vivo. The nonconjugated doxylamine metabolites isolated and identified include: doxylamine N-oxide, desmethyldoxylamine, didesmethyldoxylamine and ring-hydroxylated products of doxylamine and desmethyldoxylamine. The studies demonstrate the role of hepatic metabolism in the elimination of doxylamine succinate in the rat.

Animals↗

Metabolism of pyrilamine maleate in Fischer 344 rats, Part I: Activity excretion profiles.

Male and female Fisher 344 rats (12 per group) were dosed by gavage with either 2 or 10 mg (based on the free amine) pyrilamine maleate containing about 12 and 6 muCi 14C-pyrilamine maleate, respectively, to determine excretion of the activity as a function of dose and sex with time. Urine and feces were collected at timed intervals through 144 h. Most of the dose (about 70%) was eliminated within 48 h through the urine and feces, but only about 80% of the total dose was recovered during the experiment. Less than 1% of the total dose remained in the rats at the end of the test period. In an additional experiment to determine the location of the remainder of the dose (about 20%), male rats were dosed with 2 mg pyrilamine maleate containing 14C-pyrilamine maleate. After 144 h, exhaustive washing of the cages resulted in recovery of approximately 20% of the dose, thus identifying its location. There were no significant sex or dose related differences observed in the total amount of 14C that was eliminated through the urine or feces and recovered. Urine and feces are the major routes of elimination of pyrilamine maleate in the Fischer 344 rat. The urinary route of elimination was more predominant than the fecal route in both sexes at either dose.

Aminopyridines↗

Metabolism of doxylamine succinate in Fischer 344 rats. Part III: Conjugated urinary and fecal metabolites.

Elimination and metabolic profiles of the glucuronide products of doxylamine and its N-demethylated metabolites were determined after the oral administration of (14C)-doxylamine succinate (13.3 and 133 mg/kg doses) to male and female Fischer 344 rats. The cumulative urinary and fecal eliminations of these conjugated doxylamine metabolites at the 13.3 mg/kg dose were 44.4 +/- 4.2% and 47.3 +/- 8.1% of the total recovered dose for male and female rats, respectively. The cumulative urinary and fecal eliminations of conjugated doxylamine metabolites at the 133 mg/kg dose were 55.2 +/- 2.6% and 47.9 +/- 2.5% of the total recovered dose for male and female rats, respectively. The conjugated doxylamine metabolites that were isolated, quantitated, and identified are doxylamine O-glucuronide, N-desmethyl-doxylamine O-glucuronide, and N,N-didesmethyldoxylamine O-glucuronide.

Administration, Oral↗

Characterization of iodine derivatives of aflatoxin B1 and G1 by thermospray mass spectrometry.

Thermospray mass spectrometry (TSMS) was used to identify the derivatives formed when iodine is reacted with aflatoxins B1 and G1 at approximately 70 degrees C to enhance fluorescence. It was found that stable derivatives were formed by addition of an iodine atom and a methoxy group across the double bond located on the furan ring of the aflatoxin B1 and G1 molecules. TSMS and TSMS/MS daughter spectra of the reaction products of aflatoxin B1 and G1 with iodine provide evidence of the addition of each moiety to produce the iodo-methoxy derivative. The addition of an iodine atom to one carbon and a methoxy group to the other carbon of the furan ring provided molecular weights of 470 and 486 for the products of aflatoxin B1 and G1, respectively.

Aflatoxin B1↗

Simultaneous determination of trimellitic anhydride and its trimellitic acid impurity by GC/FID.

Trimellitic anhydride has widespread usage in a variety of industrial processes. Inhalation of the airborne dust and fumes generated by these processes is the primary route of occupational exposure leading to a variety of respiratory maladies. Because of its extensive industrial usage and limited toxicological data, trimellitic anhydride was scheduled for toxicological evaluation. Analytical purity certification and chemical characterization of the chemical were required as prerequisites for such toxicological tests. Therefore, a sensitive and specific procedure for the analysis of trimellitic anhydride and its trimellitic acid impurity in admixture was developed. After methylation with diazomethane, the compounds were assayed by gas chromatography using flame ionization detection. Chromatography on 5% SP-2100 yielded two well separated peaks, which were used for quantitation of the parent compounds. Confirmational identity of trimellitic anhydride was determined by direct insertion probe mass spectrometry, while that of the anhydride methyl derivative and trimellitic acid trimethyl derivative was determined by gas chromatography-mass spectrometry.

Diazomethane↗

Metabolism of nine benzidine-congener-based azo dyes in rats based on gas chromatographic assays of the urine for potentially carcinogenic metabolites.

Metabolism experiments were conducted with rats dosed with nine azo dyes based on dimethyl-, dimethoxy-, or dichlorobenzidine to determine whether the free amine congeners, their monoacetyl or diacetyl metabolites, or alkaline hydrolyzable conjugates were excreted in the urine. After preliminary tests of the dyes, 2-mg doses were administered to each animal and urine samples were collected at intervals up to 96 hours. EC/GC procedures were based on the analysis of heptafluorobutyryl derivatives of the free amine congener moieties or their monoacetyl metabolites. Peak levels of metabolites were excreted either 0-12 or 12-24 hours after administration and, in seven of nine instances, no metabolites persisted in the urine after 48 hours. Minimum detectable levels of all metabolites were 12 ppb or less. All nine dyes were shown to be converted to measurable levels of their benzidine-congener-based metabolites in rats.

Amines↗

Trace level determination of doxylamine in nonhuman primate plasma and urine by GC/NPD and HPLC.

Bendectin contains doxylamine succinate and is used for the treatment of nausea and vomiting in pregnant women. Trace level analytical chemical procedures for analysis of doxylamine in primate urine and plasma were required before toxicological tests with the drug in three species of nonhuman primates could be performed. A gas chromatographic procedure using a nitrogen phosphorus detector was developed to quantitate doxylamine in primate plasma at levels as low as 100 ppb. A high-pressure liquid chromatographic procedure was also developed to assay the drug in primate urine at levels as low as 250 ppb. Data from stability studies with the drug in plasma at -5 degrees and -20 degrees C, and recovery of the drug from Bendectin tablets, plasma, and urine are also presented.

Animals↗

Determination of triethylenetetramine dihydrochloride in aqueous solution by reversed-phase ion-pairing high performance liquid chromatography and conductivity detection.

Triethylenetetramine dihydrochloride (TETA) has been used for the treatment of Wilson's disease which is a metabolic disorder that prevents its victims from eliminating excess copper. TETA was scheduled for toxicological evaluation because of a deficiency of such information. Analytical chemical procedures to determine the purity of the drug as well as the proper concentration and stability of the drug in dosed water were prerequisites for the toxicological tests. A high performance liquid chromatography (HPLC) procedure employing ion-pairing and conductivity detection has been developed for the analysis of TETA in dosed water at levels as low as 10 micrograms/mL and for the determination of drug purity. The conductivity detector response was linear over the concentration range of 10 to 100 micrograms/mL. Data are presented concerning the stability of the drug in water during ambient storage and after autoclaving. An ancillary colorimetric procedure for the analysis of aqueous TETA solutions is also presented which is based on measuring the absorbance of the colored TETA copper chelate at 599 nm. The HPLC procedure is applicable to the analysis of TETA and the chemically similar polyamines spermidine and spermine in admixture.

Animals↗

Gas chromatographic-thermal energy analysis method for N-nitrosodibutylamine in latex infant pacifiers: collaborative study.

Each of 5 collaborating laboratories determined volatile N-nitrosamines in 3 blind quadruplicate sets of latex rubber infant pacifier samples, using a gas chromatographic-thermal energy analysis (GC-TEA) method. Volatile N-nitrosamines are extracted from cut-up pacifier nipples with CH2Cl2. The extract is concentrated and subjected to high temperature purge and trap, and the nitrosamines are eluted from the trap and determined by GC-TEA. N-Nitrosodibutylamine (NDBA) was the only nitrosamine found in sufficient concentration to allow analysis. NDBA concentrations of the 3 sets of samples were 82.6, 21.0, and 7.12 ng/g rubber. The repeatability relative standard deviations ranged from 7.46 to 24.0% and the reproducibility relative standard deviations from 7.46 to 29.2%. The minimum detectable level of NDBA by this method is 3.6 ng/g rubber. The method has been adopted official first action.

Chromatography, Gas↗

Volatile N-nitrosamines in infant pacifiers sold in the United States as determined by gas chromatography/thermal energy analysis.

Volatile N-nitrosamines in infant latex rubber pacifiers were determined using a modification of a previously described dichloromethane extraction procedure, followed by gas chromatography/thermal energy analysis. Under an interagency agreement between the National Center for Toxicological Research and the Consumer Product Safety Commission (CPSC), data were obtained on the baseline and compliance concentrations of volatile N-nitrosamines in infant pacifiers sold in the United States. Pacifiers made by 18 different manufacturers before and after the January 1, 1984 action level of 60 ppb was set by the CPSC were analyzed for volatile N-nitrosamines. N-Nitrosodibutylamine was the principal N-nitrosamine found, along with trace amounts of N-nitrosodimethylamine, N-nitrosodiethylamine, and N-nitrosopiperidine. Mean total volatile N-nitrosamine levels for baseline and compliance samples were 63.9 and 21.2 ppb, respectively. The pacifier lots sampled after January 1, 1984 showed a significant decrease in contamination levels, indicating that at least 98% of the market share is in compliance with the CPSC enforcement policy for N-nitrosamines in infant pacifiers sold in the United States.

Chromatography, Gas↗

High temperature purge and trap procedure for determining seven volatile N-nitrosamines in animal feed, using gas chromatography/thermal energy analyzer.

A rapid and sensitive procedure is described for determining 4 N-nitrosodialkylamines (dimethyl, diethyl, dipropyl, and dibutyl) and the N-nitroso analogs of piperidine, pyrrolidine, and morpholine in animal feed. The volatile N-nitrosamines were isolated by using a modified high temperature purge and trap apparatus designed for multiple sample cleanup. The feed sample was mixed with mineral oil and a nitrosation inhibitor, and the N-nitrosamines were purged onto a ThermoSorb/N cartridge, eluted with acetone-dichloromethane (1 + 1), and determined by gas chromatography, using a thermal energy analyzer. The effects of purge rate, purge time, and temperature on recovery are discussed. Feed samples spiked with 10, 50, and 200 ppb of the 7 N-nitroso compounds yielded recoveries ranging from 70 to 97%, with precision ranging from 1.3 to 5.4% and minimum detectable levels in the low parts-per-billion range.

Animal Feed↗

Liquid chromatographic determination of sulfadiazine in salmon by postcolumn derivatization and fluorescence detection.

A reversed-phase (ODS-2) liquid chromatographic method was developed to determine low nanogram-per-gram levels of sulfadiazine (SDZ) in salmon muscle tissue. SDZ was extracted with acetonitrile-aqueous 2% acetic acid (pH 3.0), partitioned into methylene chloride, and cleaned up by using a strong-cation-exchange, solid-phase extraction cartridge. SDZ was derivatized postcolumn with fluorescamine and detected by fluorescence. The limit of detection was 0.2 ng SDZ/g tissue. Recoveries from coho salmon tissue fortified with 1, 5, 10, and 20 ng SDZ/g tissue averaged 84.5, 85.0, 83.6, and 83.9%, respectively; recoveries from Atlantic salmon tissue fortified with 10 ng SDZ/g tissue averaged 82.6%.

Animals↗

Liquid chromatographic determination of thiamine in rodent feed by postcolumn derivatization and fluorescence detection.

A liquid chromatographic method was developed for determination of the essential nutrient thiamine (vitamin B1) in rodent feed. Thiamine was extracted with hydrochloric acid, separated by reversed-phase liquid chromatography, derivatized postcolumn to thiochrome with potassium hydroxide and potassium ferricyanide, and detected by fluorescence. Excitation and emission wavelengths were 370 and 430 nm, respectively. Detector response was linear in the range of 2.58 to 15.5 ng of thiamine injected. Instrument detection limit was 5 pg of thiamine injected.

Animal Feed↗