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PubMedDate not supplied

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↗
PubMed1989

Pharmacokinetics of doxylamine, a component of Bendectin, in the rhesus monkey.

The elimination of doxylamine and metabolites was determined after iv administration of [14C]doxylamine succinate at 0.7 and 13.3 mg/kg to the adult female rhesus monkey. Although the total recovery of radioactivity was the same for the low- and high-dose studies (90.2%), the rate of plasma elimination of doxylamine and its demethylated metabolite (desmethyldoxylamine) was slower for the high dose group. The 24 hr urinary excretion of doxylamine metabolites, desmethyl- and didesmethyldoxylamine, was significantly increased and the polar doxylamine metabolites were significantly decreased as the iv doxylamine succinate dose was increased. The plasma elimination of gas chromatograph (GC)-detected doxylamine was determined after oral administration of Bendectin (doxylamine succinate and pyridoxine hydrochloride) at 7, 13.3, and 27 mg/kg to adult female rhesus monkeys. As the dose increased, the clearance of doxylamine decreased. A statistically evaluated fit of the oral data to a single-compartment, parallel first-order elimination model and a single-compartment, parallel first- and second-order (Michaelis-Menten) elimination model indicated that the more complex model containing the second-order process was most consistent with the observed elimination data.

Animals↗
PubMedDate not supplied

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↗
PubMedDate not supplied

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↗
PubMed1989

Pharmacokinetics of doxylamine given as Bendectin in the pregnant monkey and baboon.

The object of the present study was to determine the maternal plasma pharmacokinetics of doxylamine (the antihistamine component of Bendectin) following Bendectin administration. Bendectin was administered daily, po, at a dosage approximately 10 times the maximum human therapeutic dosage (7 mg/kg/day) throughout organogenesis (approximately days 22 through 50 of gestation) to three cynomolgus monkeys, four rhesus monkeys, and five baboons. Two pharmacokinetic experiments were performed in each animal, one on the first day of treatment and one on the last day of treatment. Although this study was not designed specifically as a teratologic examination, no morphologic abnormalities were observed when the fetuses were examined on approximately day 100 of gestation. A single-compartment, parallel first- and second-order elimination model was used to analyze the data. Although considerable interindividual variation was evident, no significant differences between species were observed when the half-life for the absorption of doxylamine from the gut or the elimination of doxylamine and metabolites from the plasma were compared. The plasma elimination half-lives and the clearance values were not altered by the 29 days of Bendectin treatment for any of the species. Only the half-life for the absorption of doxylamine in the baboon was reduced by daily dosing with Bendectin, but this did not alter doxylamine elimination. Thus, the pharmacokinetics of doxylamine administered as Bendectin were similar in the three nonhuman primate species examined and were not altered by repeated daily administration.

Animals↗
PubMed1983

The general toxicology unknown. II. A case report: doxylamine and pyrilamine intoxication.

A general toxicology unknown case is presented to demonstrate our systematic approach. A 20-year-old male was found dead with multiple suicide notes. Overdose was suspected but substances were not known. Blood alcohol was negative. Urine was analyzed by enzyme-multiplied immunoassay technique and was negative for all drugs assayed. Urine was then extracted with ethyl acetate:hexane (1:1) at pH 10 and back-extracted into 1.0N sulfuric acid. The acidic layer was adjusted to pH 10, and re-extracted with ethyl acetate:hexane (1:1). The residue was analyzed by gas chromatography (GC) on a 3% OV-101 column. It was found to be negative for all commonly screened substances. However, several unknown peaks were observed. Electron impact mass spectra of these unknown peaks were obtained and searched for in our computer library of more than 25000 mass spectra. These unknown peaks were identified as doxylamine and pyrilamine by gas chromatography/mass spectrometry. The base peak and molecular ion for pyrilamine were at m/z 121 and 285, respectively. The base peak for doxylamine was at m/z 58. No molecular ion was observed for doxylamine. Both doxylamine and pyrilamine are antihistamines, but are promoted and used in the management of insomnia. Quantitation was performed on a GC using dexbrompheniramine as an internal standard. Blood concentrations for doxylamine and pyrilamine were 0.7 and 7.0 mg/L, respectively. Concentrations in other tissues were determined. Death was caused by combined doxylamine and pyrilamine intoxication; the manner of death was suicide.

Adult↗
PubMed1995

A clinical study to evaluate the efficacy of the antihistamine doxylamine succinate in the relief of runny nose and sneezing associated with upper respiratory tract infection.

Antihistamines are widely used in common cold medications, although the role of histamine in the development of common cold symptoms is unclear and the use of antihistamines for the treatment of common cold is controversial. It is clear that antihistamines do not offer a cure for common cold but they may alleviate symptoms of sneezing and runny nose. The present study was designed to investigate the efficacy of an antihistamine, doxylamine, on the symptoms of runny nose and sneezing associated with common cold. We conducted a randomized double-blind study in cold sufferers. One thousand and one volunteers with cold symptoms were screened in four centres (UK, Denmark, Belgium, Germany) and 688 satisfied the entry criteria of the study. The main reasons for excluding subjects were a low nasal secretion weight (secretion weight < 0.2g, 72%) and a low subjective rhinorrhoea score (24%). Volunteers were randomized to receive either doxylamine succinate 7.5 mg by mouth four times a day up to nine doses (n = 345) or placebo (n = 343). The principal measurements were prospectively defined as runny nose and sneezing symptom scores. Data were analysed on an intention-to-treat basis, using Cochran-Mantel-Haenszel statistics controlling for baseline symptom scores. A between-group comparison showed that doxylamine-treated volunteers benefited from a significantly greater reduction in runny nose scores (P < 0.01) and sneezing scores (P < 0.001), than those volunteers in the placebo group. Doxylamine therapy was well tolerated; the incidence of unexpected side-effects was comparable with placebo. Of the expected side-effects, 13.3% of doxylamine-treated patients reported drowsiness. The incidence of sedative effects was lower than has been reported for other commonly used first-generation antihistamines.

Common Cold↗
PubMed1987

Poisoning with over-the-counter doxylamine preparations: an evaluation of 109 cases.

One hundred and nine cases of monointoxication with doxylamine were evaluated with respect to age distribution, amount ingested, plasma level, and clinical symptomatology. The age of 60% of the patients ranged between 16 and 30 years. In about 60% of the cases 10 to 40 times a single therapeutic dose (25 mg) was ingested. Doxylamine plasma concentrations exceeded the maximum plasma level after a therapeutic dose by a factor of 10 to 40 in two-thirds of cases. The most frequent symptoms included impaired consciousness, seizures, tachycardia, mydriasis and a 'psychosis' similar to that in catatonic stupor. A serious complication may be rhabdomyolysis with subsequent impairment of renal function and acute renal failure. No symptoms were observed in 39% of the patients. No correlation was found between the amount ingested or doxylamine plasma level and the clinical symptomatology. Primary detoxication included gastric lavage, administration of activated charcoal and sodium sulfate. Regarding the high frequency of doxylamine overdose and its possible complications the question arises as to whether doxylamine-containing preparations should be subjected to prescription.

Adolescent↗
PubMed1989

Clearance of the antihistamine doxylamine. Reduced in elderly men but not in elderly women.

A single oral dose of doxylamine succinate 25 mg was administered to 21 young (20 to 43 years) and 22 elderly (60 to 87 years) volunteers. Multiple plasma doxylamine concentrations were determined during a 30-hour period after each dose. Elderly and young women did not differ significantly in peak plasma doxylamine concentration (Cmax) [116 vs 103 micrograms/L], time to Cmax (tmax) [2.4 vs 2.4 h], elimination half-life (12.2 vs 10.1 h), volume of distribution (179 vs 176 L) or clearance (191 vs 218 ml/min). Cmax (107 vs 108 micrograms/L) and tmax (2.1 vs 1.6 h) also did not differ between elderly and young men. However, elderly men had reduced doxylamine clearance (174 vs 240 ml/min, p less than 0.02; 2.5 vs 3.2 ml/min/kg, p less than 0.07) and prolonged half-life (15.5 vs 10.2 h, p less than 0.05). The reduced doxylamine clearance and prolonged half-life in elderly men, but not in elderly women, is similar to results for many other drugs which are transformed by oxidation.

Adult↗
PubMed1985

Mass spectral characterization of doxylamine and its rhesus monkey urinary metabolites.

This study describes the use of mass spectrometry (MS), high-performance liquid chromatography (HPLC) and chemical derivatization techniques for the identification of doxylamine and five rhesus monkey urinary metabolites. The analyses were performed using chemical ionization mass spectrometry with either methane or ammonia as the reagent gas. The confirmation of the structures of two of these urinary metabolites was aided by the synthesis of doxylamine N-oxide and desmethyldoxylamine and by the use of methylation and acetylation derivatization techniques. Doxylamine N-oxide, desmethyldoxylamine, didesmethyldoxylamine, and two metabolites which resulted from the cleavage of the aliphatic tertiary nitrogen side chain to the subsequent 2-[1-phenyl-1-(2-pyridinyl)ethoxy]acetic acid or 2-[1-phenyl-1-(2-pyridinyl)ethoxy]methanol compounds were isolated and identified from rhesus monkey urine. Additional data concerning the mass spectral analysis of derivatization or reaction products from the three chloroformate reactions with doxylamine, and the synthesis and separation techniques which afforded mass spectral identification of the urinary metabolites are also presented.

Animals↗
PubMed1985

The pharmacokinetics of doxylamine: use of automated gas chromatography with nitrogen-phosphorus detection.

Sixteen healthy male volunteers received a single oral dose of 25 mg doxylamine succinate. Doxylamine concentrations in plasma were measured by a newly developed gas chromatographic methodology, utilizing direct alkaline extraction into hexane:isoamyl alcohol followed by concentration and autoinjection. Doxylamine kinetics were determined from multiple plasma doxylamine concentrations measured during the 24 hours postdose. Mean kinetic variables were: peak plasma level, 99 ng/mL; time of peak, 2.4 hours postdose; elimination half-life, 10.1 hours; and apparent oral clearance, 217 mL/min. Analogous analytic methodology can be used to study the pharmacokinetics of other drugs of this class.

Adult↗
PubMed1989

Doxylamine and diphenhydramine pharmacokinetics in women on low-dose estrogen oral contraceptives.

Thirteen women chronically using low-dose estrogen-containing oral contraceptives (50 micrograms or less of ethinyl estradiol or its equivalent for a minimum of 3 months) and 12 age-matched drug-free control women received a single 25 mg oral dose of doxylamine succinate in the fasting state. Ten women taking oral contraceptives and ten controls received a single 50 mg oral dose of diphenhydramine hydrochloride. Multiple plasma samples drawn during 30 hours following the dose of doxylamine, and 12 hours after diphenhydramine dosage, were analyzed by gas chromatography using nitrogen-phosphorus detection. Mean pharmacokinetic variables for doxylamine in control and oral contraceptive groups were: peak plasma concentration, 103 vs 100 ng/ml; time of peak, 2.40 vs 1.87 hours after dosage, elimination half-life, 10.1 vs 10.2 hours; and total clearance, 3.70 vs 3.88 ml/min/kg. Mean pharmacokinetic variables for diphenhydramine in control and oral contraceptive groups were: peak plasma concentration, 63.7 vs 73.8 ng/ml; time of peak, 2.7 vs 2.2 hours after dosage; elimination half-life, 6.0 vs 5.1 hours; and total clearance, 21.8 vs 25.5 ml/min/kg. None of these differences were statistically significant. Thus, low-dose estrogen-containing oral contraceptives do not significantly influence the pharmacokinetics of the antihistamines doxylamine or diphenhydramine.

Adult↗
PubMed1987

Formation of artifactual metabolites of doxylamine following acid hydrolysis.

This study describes the use of gas chromatographic-mass spectrometric, high-performance liquid chromatographic and capillary column gas chromatographic separation techniques in demonstrating the production of several artifactual compounds reported in the literature as metabolites of doxylamine. Rhesus monkey urinary extracts which contained doxylamine and doxylamine metabolites were examined with and without acid hydrolysis. The production of 1-phenyl-1-(2-pyridinyl)ethanol and 1-phenyl-1-(2-pyridinyl)ethylene under acid hydrolysis conditions was demonstrated. These artifactual products were shown to originate from the acid hydrolysis of 2-[1-phenyl-1-(2-pyridinyl)ethoxy] acetic acid and not from doxylamine.

Animals↗
PubMed1986

Desorption chemical ionization and fast atom bombardment mass spectrometric studies of the glucuronide metabolites of doxylamine.

Three glucuronide metabolites of doxylamine succinate were collected in a single fraction using high-performance liquid chromatography (HPLC) from the urine of dosed male Fischer 344 rats. The metabolites were then separated using an additional HPLC step into fractions containing predominantly a single glucuronide metabolite. Analysis of the metabolites by methane and ammonia desorption chemical ionization, with and without derivatization, revealed fragment ions suggestive of a hydroxylated doxylamine moiety. Identification of the metabolites as glucuronides of doxylamine, desmethyldoxylamine and didesmethyldoxylamine was accomplished, based on determination of the molecular weight and exact mass of each metabolite using fast atom bombardment (FAB) ionization. This assignment was confirmed by the fragmentation observed in FAB mass spectrometric and tandem mass spectrometric experiments. Para-substitution of the glucuronide on the phenyl moiety was observed by 500-MHz nuclear magnetic resonance (NMR) spectrometry. A fraction containing all three glucuronide metabolites, after a single stage of HPLC separation, was also analysed by FAB mass spectrometry, and the proton- and potassium-containing quasimolecular ions for all three metabolites were observed.

Animals↗
PubMed1983

Analysis of doxylamine in plasma by high-performance liquid chromatography.

A rapid and sensitive high-performance liquid chromatographic (HPLC) assay for the quantitative determination of doxylamine in plasma is described. The drug levels of doxylamine in plasma were monitored after the oral administration of a single 25-mg tablet of doxylamine succinate to each of 20 male volunteers. The compound was extracted from the plasma samples, concentrated under a nitrogen stream, and analyzed by HPLC using normal-phase chromatography with detection at 254 nm. The detection limit is approximately 5 ng/ml.

Adult↗
PubMed1988

Subchronic studies of doxylamine in Fischer 344 rats.

Doxylamine succinate was administered as an admixture in the feed to male and female Fischer 344 rats for either 14 or 90 days. The 14-day study included dose levels of 0, 100, 250, 500, 1000, or 2000 ppm doxylamine. Except for a 7% decrease in final body weight in female rats in the 2000 ppm group, there were no significant clinical observations made in the 14-day study. Microscopic lesions judged to be treatment-related were limited to cytoplasmic vacuolization in the livers. The lesions were more numerous in the higher dose groups of males and present only in the 2000 ppm group of females. Dose levels of 0, 162, 405, 1012, 2530, and 6325 ppm doxylamine were administered in the 90-day study. There were no deaths during the study. Final body weights were decreased 13.3% in males of the 6325 ppm group and 5.2, 10.1, and 14.4% in females in the 1012, 2530, and 6325 ppm groups, respectively. Liver/brain weight ratios were increased in all treated male groups and in the two highest dose groups of females. Other organ weight changes were decreases and believed to result from general reduction in weight gain in those groups where the decreases occurred. Treatment-related histological changes were identified in the liver and parotid salivary gland. Cytoplasmic vacuolization or fatty change of the liver was found in all groups of males but was more severe in the higher dose groups. In females, these liver lesions were observed only in the two highest dose groups. A dose-related change in the parotid salivary gland, consisting of cytomegaly with basophilic and coarsely granular or vacuolated cytoplasm, was observed.

Animals↗
PubMed1988

Subchronic studies of doxylamine in B6C3F1 mice.

Doxylamine succinate, a histamine (H1) antagonist (antihistamine), was administered as an admixture in the feed to male and female B6C3F1 mice for 14 or 90 days. Dose levels of 0, 100, 250, 500, 1000, and 2000 ppm doxylamine were administered to males and females in the 14-day study while dose levels of 0, 80, 162, 325, 750, and 1500 ppm were administered to both sexes in the 90-day study. Little toxicity was seen in the 14-day study. Final body weights in the highest dose group were reduced 4.0 and 7.3% in males and females, respectively. Treatment-related histopathological changes in the 14-day study were limited to a very low incidence of hepatic necrosis in both sexes. There was little toxicity observed in the 90-day study and no clear dose response relative to weight gain was observed. Histologically, the liver was the only organ affected by doxylamine administration. The liver lesions consisted of hepatic cell cytomegaly and/or karyomegaly which varied from mild to severe and a possible dose-related hepatic necrosis.

Animals↗
PubMed1996

Assessment of doxylamine influence on mixed function oxidase activity upon multiple dose oral administration to normal volunteers.

The primary purpose of this study was to assess the influence of doxylamine and phenobarbital on antipyrine/metabolites pharmacokinetics and 6 beta-hydroxycortisol urinary excretion. This study was conducted in 48 healthy male human volunteers (16 per treatment group) using a parallel study design. Treatment groups consisted of 12.5 mg of doxylamine succinate, placebo, or 30 mg of phenobarbital administered orally every 6 h for 17 days. Results indicate that no statistically significant differences were observed between the doxylamine and placebo groups that are indicative of enzyme induction. For the phenobarbital group, a significant increase for antipyrine total (36 versus 45 mL/h/kg) and nonrenal (35 versus 44 mL/h/kg) clearances and 6 beta-hydroxycortisol excretion (338 versus 529 micrograms) and a significant decrease in the terminal exponential half-life (11 versus 9 h) of antipyrine were observed.

Administration, Oral↗