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Journal of Analytical Toxicology 1987Elimination and metabolic profiles of doxylamine and its nonconjugated metabolites were determined after the oral administration of [14C]-doxylamine succinate (13.3...
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.
Topics: Animals; Bacteria; Chromatography, Gas; Chromatography, High Pressure Liquid; Dose-Response Relationship, Drug; Doxylamine; Feces; Female; In Vitro Techniques; Intestinal Mucosa; Liver; Magnetic Resonance Spectroscopy; Male; Mass Spectrometry; Pyridines; Rats; Rats, Inbred F344
PubMed: 3599917
DOI: 10.1093/jat/11.3.113 -
Reproductive Toxicology (Elmsford, N.Y.) 1989The 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...
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.
Topics: Animals; Chromatography, Gas; Chromatography, High Pressure Liquid; Dicyclomine; Doxylamine; Drug Combinations; Female; Half-Life; Intestinal Absorption; Macaca mulatta; Models, Biological; Pyridoxine
PubMed: 2520522
DOI: 10.1016/0890-6238(89)90006-3 -
Environmental Technology Feb 2024N-nitrosodimethylamine (NDMA) is a disinfection byproduct that forms at the presence of an organic nitrogen precursor. Doxylamine, an antihistaminic pharmaceutical, is a...
N-nitrosodimethylamine (NDMA) is a disinfection byproduct that forms at the presence of an organic nitrogen precursor. Doxylamine, an antihistaminic pharmaceutical, is a precursor of NDMA and has been shown to form NDMA in the presence of chloramine. In this study, the effect of Doxylamine as an NDMA precursor has been further studied during chloramination. The end product and byproducts during chloramination were investigated using a high-resolution mass spectrometer by taking samples at different time intervals. Results suggest that NDMA is not the only end product forming during chloramination of Doxylamine and several transformation products that do not end up as NDMA may form. A group of these transformation products have been selected based on their relative amounts during chloramination with time and notated as Focus Tentative Transformation Products (FTTP). The identification of these byproducts will make it easier to study the conditions during chloramination that may favour these known' transformation products with the use of less sophisticated analytical instruments. Then, it might lead to the establishment of chloramination protocols that will minimise the formation of NDMA from its precursors.
Topics: Dimethylnitrosamine; Doxylamine; Nitrogen; Disinfection; Water Purification; Water Pollutants, Chemical
PubMed: 36222397
DOI: 10.1080/09593330.2022.2135462 -
Journal of Clinical Pharmacology Mar 1989Thirteen women chronically using low-dose estrogen-containing oral contraceptives (50 micrograms or less of ethinyl estradiol or its equivalent for a minimum of 3... (Comparative Study)
Comparative Study
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.
Topics: Adult; Diphenhydramine; Doxylamine; Ethinyl Estradiol; Female; Half-Life; Humans; Metabolic Clearance Rate; Pyridines
PubMed: 2723113
DOI: 10.1002/j.1552-4604.1989.tb03323.x -
Cureus Aug 2023A 52-year-old male with acute onset right-sided weakness, numbness, and buttock pain after consuming 30 tablets of doxylamine antihistamine the night prior. Laboratory...
A 52-year-old male with acute onset right-sided weakness, numbness, and buttock pain after consuming 30 tablets of doxylamine antihistamine the night prior. Laboratory tests showed elevated creatinine kinase, blood urea nitrogen, creatinine, troponins, liver transaminases, and phosphate. The patient was admitted to the medical intensive care unit for severe rhabdomyolysis, acute liver failure, and acute kidney injury secondary to doxylamine intoxication. Studies describe symptoms of severe doxylamine intoxication, such as impaired consciousness (coma), grand mal seizures, and cardiopulmonary arrest. Circulating myoglobin causes oxidative injury to the kidney through the formation of F2-isoprostanes leading to renal vasoconstriction. One study explained drug-induced rhabdomyolysis via two mechanisms: direct drug injury to the striated muscle and local muscle compression in seizure, coma, and metabolic abnormality. Treatment involves aggressive hydration with monitoring of serum electrolytes and renal function. Aggressive volume expansion via intravenous fluids remains critical in preventing rhabdomyolysis-associated nephrotoxicity and myoglobin-induced acute renal failure. Alkalinization of urine may prevent renal vasoconstriction resulting in enhanced excretion of the toxic metabolites of doxylamine and myoglobin via renal tubules, thereby reducing peak serum concentration time and preventing direct renal tissue damage.
PubMed: 37581198
DOI: 10.7759/cureus.43395 -
The Journal of Pharmacy and Pharmacology Dec 2018The aim of this experiment was mainly to examine the effects of intrathecally injected doxylamine and triprolidine, two antihistamine drugs spinal motor and sensory...
OBJECTIVES
The aim of this experiment was mainly to examine the effects of intrathecally injected doxylamine and triprolidine, two antihistamine drugs spinal motor and sensory functions.
METHODS
After intrathecally injecting the rats with five different doses, the dose-response curves of spinal sensory and motor block with doxylamine and triprolidine were constructed. In comparison with the local anaesthetic mepivacaine, the quality and duration of spinal anaesthesia with doxylamine or triprolidine were conducted.
KEY FINDINGS
Doxylamine, mepivacaine and triprolidine elicited spinal motor and sensory (nociception and proprioception) blockades in a dose-dependent fashion. On the ED (50% effective dose) basis, the rank order of drug potency was triprolidine > mepivacaine > doxylamine (P < 0.05) at provoking spinal motor, proprioceptive and nociceptive blockades. On the equianaesthetic doses (ED , ED and ED ), the duration of spinal anaesthesia with doxylamine was longer (P < 0.01) than that with mepivacaine or triprolidine. Moreover, doxylamine or triprolidine displayed greater potency (ED ) (P < 0.05) and duration (P < 0.05) of sensory block over motor block.
CONCLUSIONS
Doxylamine or triprolidine produces a dose-dependent effect of spinal motor and sensory block. Triprolidine with a better nociception-selective action over motor block has a better potency than mepivacaine or doxylamine. Doxylamine and triprolidine produce longer durations than mepivacaine.
Topics: Anesthetics, Local; Animals; Dose-Response Relationship, Drug; Doxylamine; Histamine Antagonists; Injections, Spinal; Male; Mepivacaine; Motor Activity; Movement; Nerve Block; Nociception; Proprioception; Rats; Rats, Sprague-Dawley; Triprolidine
PubMed: 30251371
DOI: 10.1111/jphp.13017 -
Reproductive Toxicology (Elmsford, N.Y.) 1989The object of the present study was to determine the maternal plasma pharmacokinetics of doxylamine (the antihistamine component of Bendectin) following Bendectin... (Comparative Study)
Comparative Study
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.
Topics: Animals; Chromatography, Gas; Dicyclomine; Doxylamine; Drug Combinations; Female; Half-Life; Macaca fascicularis; Macaca mulatta; Papio; Pregnancy; Pregnancy, Animal; Pyridoxine
PubMed: 2520523
DOI: 10.1016/0890-6238(89)90007-5 -
The Medical Letter on Drugs and... Dec 2018
Review
Topics: Antidepressive Agents; Benzodiazepines; Chronic Disease; Cognitive Behavioral Therapy; Humans; Hypnotics and Sedatives; Plant Preparations; Receptors, Melatonin; Sleep Initiation and Maintenance Disorders
PubMed: 30625122
DOI: No ID Found -
Lancet (London, England) Feb 1987
Topics: Adolescent; Adult; Doxylamine; Female; Humans; Male; Pyridines; Rhabdomyolysis; Suicide, Attempted
PubMed: 2880231
DOI: 10.1016/s0140-6736(87)90138-3 -
Human & Experimental Toxicology Aug 2007The objective of this prospective study was to identify risk factors for developing rhabdomyolysis in patients with doxylamine overdose. Patients who were admitted to a...
The objective of this prospective study was to identify risk factors for developing rhabdomyolysis in patients with doxylamine overdose. Patients who were admitted to a university teaching hospital between July 2000 and September 2005 due to doxylamine overdose were recruited. Demographic information, clinical variables, and laboratory data were investigated. Twenty-seven (M/F 12/15, age 33.2 +/-13.1 years) patients were enrolled. Sixteen (59%) of 27 patients developed rhabdomyolysis and three (19%) of 16 patients with rhabdomyolysis also developed acute renal failure. Patients who developed rhabdomyolysis differed from those who did not in the amount of doxylamine ingested, initial serum creatitnine and arterial pH. In multivariate regression analysis, the only reliable predictor of rhabdomyolysis was the amount of doxylamine ingested (P = 0.039). The amount of doxylamine ingested (>/= 20 mg/kg) predicted the development of rhabdomyolysis with a sensitivity of 81%, a specificity of 82%, a positive predictive value of 87%, and a negative predictive value of 75%.In conclusion, rhabdomyolysis following doxylamine overdose was common, occurring in 87% of patients who ingested more than 20 mg/kg. The amount of doxylamine ingested was the only reliable predictor for developing rhabdomyolysis following doxylamine overdose.
Topics: Acute Kidney Injury; Adult; Creatinine; Dose-Response Relationship, Drug; Doxylamine; Drug Overdose; Female; Histamine Antagonists; Humans; Hydrogen-Ion Concentration; Male; Middle Aged; Predictive Value of Tests; Prospective Studies; ROC Curve; Rhabdomyolysis; Risk Factors; Sensitivity and Specificity
PubMed: 17884948
DOI: 10.1177/0960327107077507