Abstract:
Domoic acid (DA), a potent neurotoxin produced by algae from the Pseudo-nitzschia family, presents an emerging threat to public health. Human consumption of shellfish contaminated with large doses of DA may result in Amnesiac Shellfish Poisoning, a syndrome with symptoms including short-term memory loss, seizures, and death. Though studied in rodent models, the disposition characteristics of human ingestion of DA near the EPA’s Tolerable Daily Intake, 0.075 mg/kg, are principally unknown. Thus, as part of a larger reproductive and neurodevelopmental study, we worked to determine the bioavailability and distribution kinetics of a low dose of DA in a species closely related to humans to potentially model and predict human dose-exposure relationships. Three healthy, adult, female Macaca fascicularis were intravenously injected with 0.005 mg/kg of DA in our initial study. In a follow-up study, the same 3 females were administered oral doses of 0.15 mg/kg DA. Blood plasma was collected up to eleven time points over 48 hours, and DA concentrations were measured via LC-MSMS. The i.v. study produced data consistent with findings from previous work, with no visible observed side effects. The disposition of DA displayed two-compartmental kinetics with a terminal half-life of one hour and levels below detection limit (0.05 ug/mL) at four hours. Additionally, the clearance of DA closely matched the glomerular filtration rate in macaques, suggesting primary excretion via renal clearance. Following oral administration, a prolonged exposure with a terminal half-life upwards of 18 hours was observed. The oral bioavailability of DA was 9-12%. From the pattern of DA disposition observed in these studies, we hypothesize that DA will accumulate when administered chronically despite low doses and minimal oral bioavailability. Studies using chronic exposures are currently underway to test this hypothesis. The first of its kind, this study not only demonstrated a higher oral bioavailability in primates than previously hypothesized, but also revealed that DA displays oral flip-flop kinetic patterns, possibly resulting in plasma accumulation of DA during chronic dosing.
URI