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Toxicokinetics of Domoic Acid in Cynomolgus Monkeys
Author(s) -
Jing Jing,
Petroff Rebekah,
Crouthamel Brenda,
Grant Kimberly,
Burbacher Thomas,
Isoherranen Nina
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.712.7
Subject(s) - toxicokinetics , bioavailability , domoic acid , pharmacology , dosing , neurotoxin , pharmacokinetics , chemistry , toxicity , biology , medicine , biochemistry , toxin
Objectives Domoic acid (DA), a potent neurotoxin, is produced by various marine algae and diatoms. DA acts as an analog of the neurotransmitter glutamate and is excitotoxic in the central nervous system and other glutamate receptor‐rich organs. Multiple DA intoxication cases have been reported worldwide in both marine animals and humans due to the increase of DA producing algal blooms. However, the toxicokinetics of DA has not yet been characterized in humans and it is unclear how well different animal models reproduce DA disposition in humans. In addition, due to the low assay sensitivity of DA, no toxicokinetic studies have been conducted at doses close to the tolerable daily intake (TDI) of DA in humans (0.075 ppm). The aim of this study was to determine the bioavailability and distribution and elimination kinetics of DA at doses close to the TDI in the cynomolgus monkey, a non‐human primate model for toxicokinetic studies. Methods Three healthy female adult cynomolgus monkeys (5.1±1.9 kg) were included in this study. DA was administered in a crossover design as an IV bolus of 0.005 mg/kg or as an oral solution in sugary water (0.075 mg/kg and 0.15 mg/kg, the TDI and 2* TDI in humans) with and without concomitant food. Plasma samples were collected before dosing and up to 48 hr post‐dosing. A novel LC‐MS/MS method was developed to measure DA concentrations in plasma. Results The elimination of DA from plasma after IV dosing was biphasic with alpha half‐life of 6.0 ± 4.3 min and beta half‐life of 59.6 ± 2.7 min. The clearance of DA was 2.7 ± 0.7 ml/min/kg. The clearance of DA is similar to the reported glomerular filtration rate in cynomolgus monkeys (3.1 ± 0.5 ml/min/kg) suggesting that the renal clearance of DA is primarily through filtration. The mean absolute bioavailability of DA was 13.7 % and food had no effect on DA absorption kinetics. After oral administration, the absorption of DA was slow with T max of 5.0 ± 4.3 hr and C max of 5.6 ± 1.1 ng /ml. The disposition of DA after oral dosing was characterized by flip‐flop kinetics with absorption half‐life of 16.7 ± 5.2 hr and elimination half‐life of 53.7 ± 17.4 min. Conclusions For the first time, our study fully characterized the toxicokinetics of DA in non‐human primates. The obtained toxicokinetic parameters could be further used to predict DA disposition in human and evaluate human exposure to DA. Support or Funding Information This research was funded by NIH grants P51OD010425 and 1R01ES023043‐01A1.