Format

Send to

Choose Destination
Drug Metab Dispos. 2018 Feb;46(2):155-165. doi: 10.1124/dmd.117.078485. Epub 2017 Nov 17.

Toxicokinetics and Physiologically Based Pharmacokinetic Modeling of the Shellfish Toxin Domoic Acid in Nonhuman Primates.

Author information

1
Department of Pharmaceutics (J.J., S.S., A.R.T., N.I.), Department of and Environmental and Occupational Health Sciences (R.P., B.C., K.S.G., T.M.B.), Center on Human Development and Disability (K.S.G., T.M.B.), and Infant Primate Research Laboratory, Washington National Primate Research Center, University of Washington, Seattle, Washington (K.S.G., T.M.B.).
2
Department of Pharmaceutics (J.J., S.S., A.R.T., N.I.), Department of and Environmental and Occupational Health Sciences (R.P., B.C., K.S.G., T.M.B.), Center on Human Development and Disability (K.S.G., T.M.B.), and Infant Primate Research Laboratory, Washington National Primate Research Center, University of Washington, Seattle, Washington (K.S.G., T.M.B.) ni2@uw.edu.

Abstract

Domoic acid (DA), a neurotoxin, is produced by marine algae and has caused toxications worldwide in animals and humans. However, the toxicokinetics of DA have not been fully evaluated, and information is missing on the disposition of DA following oral exposures at doses that are considered safe for human consumption. In this study, toxicokinetics of DA were investigated in cynomolgus monkeys following single doses of 5 µg/kg DA intravenously, 0.075 mg/kg DA orally, and 0.15 mg/kg DA orally. After intravenous dosing, DA had a systemic clearance of 124 ± 71 (ml/h)/kg, volume of distribution at steady state of 131 ± 71 ml/kg and elimination half-life of 1.2 ± 1.1 hours. However, following oral dosing, the average terminal half-life of DA was 11.3 ± 2.4 hours, indicating that DA disposition follows flip-flop kinetics with slow, rate-limiting absorption. The absorption of DA was low after oral dosing with absolute bioavailability of 6% ± 4%. The renal clearance of DA was variable [21-152 (ml/h)/kg] with 42% ± 11% of the intravenous DA dose recovered in urine. A physiologically based pharmacokinetic model was developed for DA in monkeys and humans that replicated the flip-flop kinetics observed after oral administration and allowed simulation of urinary excretion and brain and kidney distribution of DA following intravenous and oral dosing. This study is the first to characterize DA disposition at exposure levels close to the current estimated tolerable daily intake and to mechanistically model DA disposition in a model species, providing important information of the toxicokinetics of DA for human safety assessment.

PMID:
29150543
PMCID:
PMC5776359
DOI:
10.1124/dmd.117.078485
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center