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

• Published in: Journal of analytical toxicology Vol. 10; no. 3; p. 87
• Main Authors: Slikker, Jr, W, Holder, C L, Lipe, G W, Korfmacher, W A, Thompson, Jr, H C, Bailey, J R
• Format: Journal Article
• Language: English
• Published: England 01.05.1986
• Subjects: Animals; Carbon Radioisotopes; Chromatography, High Pressure Liquid; Dealkylation; Deamination; Doxylamine - analogs & derivatives; Doxylamine - metabolism; Female; Histamine H1 Antagonists - metabolism; Macaca mulatta; Mass Spectrometry; Pyridines - metabolism
• ISSN: 0146-4760

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.