Toxicokinetics of domoic acid in a nonhuman primate model (Macaca fascicularis)

Thesis (Master's)--University of Washington, 2016-06

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 with high concentrations of DA may result in Amnesiac Shellfish Poisoning, a syndrome with symptoms including short-term memory loss, seizures, and death. As a result, current regulations limit consumption of DA to 0.075 mg/kg/day. However, recent work has demonstrated that DA acts as a neurodevelopmental toxin in fetal and neonatal rodents, even at low doses. Yet how these effects translate to humans is unknown. An essential first step to determining if DA is a human developmental neurotoxin is understanding the basic maternal-fetal disposition of DA. Thus as part of a larger reproductive and neurodevelopmental study, this study aimed to determine the bioavailability, elimination, and distribution kinetics of a low dose of DA in a species closely related to humans, to eventually model and predict human dose-exposure relationships. Three healthy, nonpregnant, adult, female Macaca fascicularis were intravenously injected with 0.005 mg/kg of DA in our initial study. In two follow-up studies, the same 3 females were administered oral doses of 0.15 mg/kg DA, double the tolerable daily intake (TDI) in humans, and then 0.075 mg/kg DA. Plasma was collected up to 48 hours after dosing, and DA concentrations were measured by LC-MS/MS. The i.v. study produced data consistent with findings from previous work, with no visible observed side effects. The i.v. disposition of DA showed two-compartmental kinetics with a terminal half-life of one hour and levels below the limit of quantification (0.622 μg/mL) at four hours. Following oral administration, the exposure of DA was prolonged due to rate-limiting slow absorption, with a terminal half-life greater than 15 hours. The oral bioavailability of DA was 9-12%. From the pattern of DA disposition observed in these studies, we hypothesize that even low doses of DA will accumulate in plasma when administered chronically. Current studies using chronic exposures are 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 kinetics characterized by a rate limiting absorption phase, resulting in the plasma accumulation of DA during chronic dosing but lower peak concentrations than would be expected if rapidly absorbed. Because current regulations for human consumption are based on the hypothesis that the exposure from DA is short, these results may indicate a higher risk for neurodevelopmental effects following in utero DA exposure.