Plasma Protein and Lipoprotein Binding of Cis- and Trans-Permethrin and Deltamethrin in Adult Humans and Rats.

The majority of residents of the United States, Canada, and Europe are exposed to pyrethroids, the most commonly used class of insecticides. Surprisingly little is known about key aspects of their pharmacokinetics, including their mode of transport in the systemic circulation. This study tested the hypothesis that pyrethroids are transported by both plasma lipoproteins and proteins, similarly to other highly lipophilic environmental contaminants. Other aims were to characterize the binding of representative type I and II pyrethroids, and to compare their binding to rat versus human plasma. Binding of 14C-labeled cis-permethrin (CIS), trans-permethrin (TRANS) and deltamethrin (DLM) to proteins and lipoproteins was measured by sequential extraction of spiked plasma with isooctane, 2-octanol, and acetonitrile. Binding of DLM, CIS, and TRANS to plasma proteins and lipoproteins was linear from 250 to 750 nM; concentrations present in the plasma of orally dosed rats. Binding of DLM to high-density lipoprotein was twice that to low-density lipoprotein. Binding of DLM, CIS, and TRANS was ∼2-fold greater to proteins than to lipoproteins of rat and human plasma; albumin was primarily responsible for protein binding. Higher total binding of each pyrethroid to human (∼90%) than to rat (∼80%) plasma resulted from higher protein binding in human plasma. This was attributable in part to the higher albumin/protein content of human plasma. Rat albumin exhibited lower pyrethroid binding capacity than did human albumin. The results of this investigation indicate that albumin and lipoproteins play a major role in binding and transport of pyrethroids in the systemic circulation of both rats and humans.

Age Dependency of Blood-Brain Barrier Penetration by cis- and trans-Permethrin in the Rat.

Permethrin (PER), a type I pyrethroid, is the most widely used insecticide in domestic settings in the United States. The overall objective of this study was to assess the efficiency of the blood-brain barrier (BBB) as an obstacle to the 14C-cis-permethrin (CIS) and 14C-trans-permethrin (TRANS) isomers of PER, and to determine whether its barrier function changes during maturation of the rat. Experiments were conducted to quantify brain uptake of CIS and TRANS in postnatal day 145, 21, and 90 Sprague-Dawley rats. The common carotid artery of anesthetized rats was perfused for 2 or 4 minutes with 1, 10, or 50 µM 14C-CIS or 14C-TRANS in 4% albumin. Brain deposition of each isomer was inversely related to age, with levels in the youngest animals >5 times those in adults. Brain uptake was linear over the 50-fold range of pyrethroid concentrations, indicative of passive, nonsaturable BBB permeation. The extent of uptake of toxicologically relevant concentrations of CIS and TRANS was quite similar. Thus, dissimilar BBB permeation does not contribute to the greater acute neurotoxic potency of CIS, but greater permeability of the immature BBB to CIS and TRANS may contribute to the increased susceptibility of preweanling rodents to the insecticides.

Gas chromatography/negative chemical ionization mass spectrometry of transfluthrin in rat plasma and brain.

RATIONALE: Transfluthrin is a relatively non-toxic rapid-acting synthetic pyrethroid insecticide. It is widely used in household and hygiene products. A sensitive and accurate bioanalytical method is required for quantification of its concentration in plasma and its potential target organ, the brain for studies to assess its health effects and toxicokinetics in mammals. METHODS: The samples were prepared by liquid-liquid extraction. Gas chromatography mass spectrometry (GC/MS) analysis was performed for the determination of transfluthrin in biological samples with an overall method run time of 15 min. Transfluthrin was quantified using selected-ion monitoring (SIM) in the negative chemical ionization (NCI) mode. Chromatographic separation was achieved using a Zebron® ZB5-MS GC column operating with 1 mL/min constant flow helium. Cis-Permethrin was used as the internal standard. RESULTS: The method was validated to be precise and accurate within the linear range of 1.0-400.0 ng/mL in plasma and 4.0-400.0 ng/mL in brain homogenate, based on a 100 µL sample volume for both matrices. This method was applied to samples following administration of a 10 mg/kg oral dose to male adult rats. The plasma concentrations were observed to be 11.70 ± 5.69 ng/mL and brain concentrations 12.09 ± 3.15 ng/g when measured 2 h post-dose. CONCLUSIONS: A rapid GC/NCI-MS method was demonstrated to be sensitive, specific, precise and accurate for the quantification of transfluthrin in rat plasma and brain. The optimized method was successfully used to quantify the rat plasma and brain concentrations of transfluthrin 2 h after the oral dosing of Sprague-Dawley rats.

Brain uptake of deltamethrin in rats as a function of plasma protein binding and blood-brain barrier maturation.

Pyrethroids, including permethrin and deltamethrin (DLM), are very widely used of insecticides. It was hypothesized that lower plasma binding and increased blood-brain barrier (BBB) penetration of DLM in immature rats contribute to the higher brain concentrations of DLM and more pronounced neurotoxicity reported in this age group. The left brain of anesthetized adult rats was perfused for 2min via a carotid artery with 1µM 14C-DLM in: 2-5% human serum albumin (HSA); plasma from adult and 15- and 21-d-old rats; and plasma from human donors of: birth-1 week, 1-4 weeks, 4 weeks-1 year, 1-3 years and adults. The fraction of DLM bound and brain uptake of DLM did not vary significantly with the HSA concentration nor with the age of rat or human plasma donors. One, 10 and 50µM 14C-DLM were perfused into the left-brain of anesthetized adult, 15- and 21-d-old rats. DLM deposition in the brain was linear over this range of concentrations and inversely related to age. The results of this investigation indicate that increased BBB permeability in the youngest rats enhances brain deposition of the insecticide. Plasma protein binding of DLM in immature rats and humans is not sufficiently diminished to impact its brain uptake.

Influence of Maturation on In Vivo Tissue to Plasma Partition Coefficients for Cis- and Trans-Permethrin.

Permethrin, the most widely used household insecticide in the United States, is marketed as a mixture of its cis (CIS) and trans (TRANS) isomers. The major objective of this investigation is to develop and utilize a reliable approach to determine in vivo partition coefficients (PCs) for CIS and TRANS in immature and adult Sprague-Dawley rats. Adult, postnatal day (PND) 21, and PND 15 rats were infused with environmentally relevant concentrations of CIS or TRANS via a subcutaneous osmotic pump for 48 or 72 h. The adult and PND 21 rats also received an oral loading dose. Systemic steady-state or equilibrium was attained in each age group within 72 h of the protocol. CIS and TRANS were both distributed to tissues according to their neutral lipid content, with adipose tissue exhibiting much higher tissue:plasma PCs than skeletal muscle, liver, or brain. Liver:plasma and brain:plasma PCs were consistently at or lower than unity. Tissue:plasma PCs were generally higher for CIS than for TRANS, although the isomers are of comparable lipophilicity. Significantly higher blood levels of CIS apparently saturate plasma binding, resulting in greater tissue deposition of the isomer. CIS and TRANS tissue:plasma PCs were found to be inversely related to the rats' age, although TRANS brain:plasma PCs were comparable in immature and mature animals. These data support the conclusion that age-dependent partitioning is an important determinant of the pharmacokinetics of permethrin. Such partitioning could influence the risk assessment of these insecticides in infants and children when incorporated into physiologically based pharmacokinetic models.