Elimination Kinetics of Domoic Acid from the Brain and Cerebrospinal Fluid of the Pregnant Rat

Fuquay, Jennifer Maucher; Muha, Noah; Wang, Zhihong; Ramsdell, John S.

doi:10.1021/tx300434s

Cited by 17 publications

(9 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The developed monkey PBPK model was also used to simulate the brain and kidney concentrations of DA following intravenous and oral doses of DA. DA concentrations were previously reported in the kidney, liver, heart, and hippocampus of mice (Funk et al, 2014) and in brain and cerebrospinal fluid in pregnant rats (Maucher Fuquay et al, 2012a). The simulated brain and kidney distribution in monkeys is in excellent agreement with prior data from rats showing rapid distribution of DA into tissues after intravenous dosing (Maucher Fuquay et al, 2012a).…”

Section: Discussionsupporting

confidence: 87%

“…DA concentrations were previously reported in the kidney, liver, heart, and hippocampus of mice (Funk et al, 2014) and in brain and cerebrospinal fluid in pregnant rats (Maucher Fuquay et al, 2012a). The simulated brain and kidney distribution in monkeys is in excellent agreement with prior data from rats showing rapid distribution of DA into tissues after intravenous dosing (Maucher Fuquay et al, 2012a). The simulated fast distribution to the brain is also in agreement with the fast onset of vomiting (2-14 minutes) in monkeys dosed with 50 mg/kg intravenously and the duration of the vomiting restricted to the first Fig.…”

Section: Discussionmentioning

confidence: 65%

“…For DA distribution, a full PBPK model was used. A K p value for brain was assigned according to the reported AUC brain / AUC plasma ratio in pregnant rats (Maucher Fuquay et al, 2012a). For kidney, liver, and heart, K p values were estimated based on the reported concentrations in mice (Funk et al, 2014).…”

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

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

Jing¹,

Petroff²,

Shum³

et al. 2017

Drug Metab Dispos

View full text Add to dashboard Cite

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 g/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.

show abstract

Section: Discussionsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 65%

See 1 more Smart Citation

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

Jing¹,

Petroff²,

Shum³

et al. 2017

Drug Metab Dispos

View full text Add to dashboard Cite

show abstract

“…The addition of 100 lM glutamate in the perfusion medium did not inhibit the brain uptake of KA or DHK suggesting that x G À does not mediate KA and DHK brain uptake. In addition, another structural analogue of KA and DHK, domoic acid has been shown to cross the BBB without the involvement of x G À in the uptake process [19,20]. This is further evidence that KA and DHK brain uptake is not x G À -mediated.…”

Section: Discussionmentioning

confidence: 72%

Blood–Brain Barrier Permeability and Brain Uptake Mechanism of Kainic Acid and Dihydrokainic Acid

et al. 2014

View full text Add to dashboard Cite

The glutamatergic neurotransmitter system is involved in important neurophysiological processes and thus constitutes a promising target for the treatment of neurological diseases. The two ionotropic glutamate receptor agonists kainic acid (KA) and dihydrokainic acid (DHK) have been used as research tools in various in vivo central nervous system disease models in rodents, as well as being templates in the design of novel ligands affecting the glutamatergic system. Both molecules are highly polar but yet capable of crossing the blood-brain barrier (BBB). We used an in situ rat brain perfusion technique to determine the brain uptake mechanism and permeability across the BBB. To determine KA and DHK concentrations in the rat brain, simple and rapid sample preparation and liquid chromatography mass spectrometer methods were developed. According to our results the BBB permeability of KA and DHK is low, 0.25 × 10(-6) and 0.28 × 10(-6) cm/s for KA and DHK, respectively. In addition, the brain uptake is mediated by passive diffusion, and not by active transport. Furthermore, the non-specific plasma and brain protein binding of KA and DHK was determined to be low, which means that the unbound drug volume of distribution in brain is also low. Therefore, even though the total KA and DHK concentrations in the brain are low after systemic dosing, the concentrations in the vicinity of the glutamate receptors are sufficient for their activation and thus the observed efficacy.

show abstract

“…While the literature base is relatively small, a theme of heightened fetal sensitivity characterized by hippocampal injury and neurological effects can be extracted from the literature (for reviews see Costa et al, 2010;Lefebvre and Robertson, 2010;Doucette et al, 2016). Domoic acid readily crosses the placenta and enters the fetal brain but does not produce structural malformations in exposed pups (Maucher Fuquay et al, 2012). Despite cessation of DA exposure at birth, progressive damage to regions of the hippocampus have been documented over the first 30 days of postnatal life (Dakshinamurti et al, 1993).…”

Section: Introductionmentioning

confidence: 99%

Preclinical Modeling of Exposure to a Global Marine Bio-Contaminant: Effects of In Utero Domoic Acid Exposure on Neonatal Behavior and Infant Memory

Grant

Crouthamel

Kenney

et al. 2018

Preprint

View full text Add to dashboard Cite

Domoic Acid (DA) is a naturally-occurring marine neurotoxin that is increasingly recognized as an important public health issue. Prenatal DA exposure occurs through the maternal consumption of contaminated shellfish/finfish. To better understand the fetal risks associated with DA, we initiated a longitudinal, preclinical study focused on the reproductive and developmental effects of chronic, low-dose oral DA exposure. To this end, 32 adult female Macaca fascicularis monkeys were orally dosed with 0, 0.075 or 0.15 mg/kg/day DA on a daily basis throughout breeding and pregnancy. The doses included the proposed human Tolerable Daily Intake (TDI) (0.075 mg/kg/day) for DA. Adult females were bred to nonexposed males. To evaluate behavioral development during early infancy, offspring were administered a neonatal exam modeled after the human Neonatal Behavior Assessment Scale and a series of visual recognition memory problems. Results indicated that DA does not impact early survival reflexes or responsivity to the environment during the neonatal period. Findings from recognition memory tests showed that exposed and control infants demonstrated robust novelty scores when test problems were relatively easy to solve. However, infants in the 0.15 mg/kg DA group failed to demonstrate a novelty response when problems became more challenging. This study is the first to evaluate the offspring neurodevelopmental effects of prenatal DA exposure in a translational primate model and results indicate subtle but significant consequences on emerging memory processes.

show abstract

Elimination Kinetics of Domoic Acid from the Brain and Cerebrospinal Fluid of the Pregnant Rat

Cited by 17 publications

References 35 publications

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

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

Blood–Brain Barrier Permeability and Brain Uptake Mechanism of Kainic Acid and Dihydrokainic Acid

Preclinical Modeling of Exposure to a Global Marine Bio-Contaminant: Effects of In Utero Domoic Acid Exposure on Neonatal Behavior and Infant Memory

Contact Info

Product

Resources

About