TY - JOUR T1 - Toxicokinetics and Physiologically Based Pharmacokinetic Modeling of the Shellfish Toxin Domoic Acid in Nonhuman Primates JF - Drug Metabolism and Disposition JO - Drug Metab Dispos DO - 10.1124/dmd.117.078485 SP - dmd.117.078485 AU - Jing Jing AU - Rebekah Petroff AU - Sara Shum AU - Brenda Crouthamel AU - Ariel R Topletz AU - Kimberly S Grant AU - Thomas M Burbacher AU - Nina Isoherranen Y1 - 2017/01/01 UR - http://dmd.aspetjournals.org/content/early/2017/11/17/dmd.117.078485.abstract N2 - Domoic acid (DA), a neurotoxin, is produced by marine algae and has caused toxications worldwide in animals and humans. However, the toxicokinetics of DA has 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 iv, 0.075 mg/kg DA po and 0.15 mg/kg DA po. Following iv dosing, DA had a systemic clearance of 124 ± 71 ml/hr/kg, volume of distribution at steady state of 131±71 ml/kg and elimination half-life of 1.2±1.1 hours. However, following po 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 po dosing with absolute bioavailability of 7 ± 4%. The renal clearance of DA was variable (21-152 ml/hr/kg) with 42±11% of the DA iv dose recovered in urine. A physiologically based pharmacokinetic (PBPK) 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 iv and po dosing. This study is the first to characterize DA disposition at exposure levels close to the current estimated Tolerable Daily Intake (TDI) and to mechanistically model DA disposition in a model species, providing important information of the toxicokinetics of DA for human safety assessment. ER -