Characterization of disposition of deltamethrin, cis-permethrin and trans-permethrin as a function of age in sprague-dawley rats
MetadataShow full item record
Although the blood and tissue partition coefficients (PCs) for pyrethroids in adult rats have previously been published, no one has evaluated the influence of maturation on the systemic disposition of pyrethroids in rats. This series of studies addressed this deficit by testing the hypothesis that the distribution of pyrethroids in immature rats will be significantly different from that in adults. Steady-state levels of deltamethrin (DLM), cis-permethrin (CIS) and trans-permethrin (TRANS) were obtained using subcutaneously implanted Alzet pumps® in Sprague-Dawley (SD) rats. For all three compounds, fat exhibited far higher PC values than brain, liver and skeletal muscle in adult rats. Brain and liver exhibited the lowest PCs followed by skeletal muscle. For all three compounds, the tissue:plasma PCs in PND 15 pups were found to be significantly higher than in adult rats. Alternatively, there was no distinct pattern, in the differences in tissue:plasma PCs between PND 21 and adult rats. An in situ brain perfusion technique was utilized to selectively investigate the role of plasma binding, membrane transporters and the blood brain barrier (BBB) on the brain uptake of DLM. The data suggested that under normal physiological conditions, plasma binding along with the BBB plays a protective role in restricting the entry of DLM into the brain. At physiological albumin concentrations and low exposure levels, a passive, non-saturable transport of DLM predominates at the BBB. Brain uptake of DLM was determined as a function of age-dependent changes in plasma protein binding and the BBB integrity. Adult brain uptake of DLM from pediatric and adult rat and human plasmas did not vary significantly. When measured as a function of the BBB integrity, uptake in PND 15 and PND 21 pups was significantly greater than in adults. The data presented here demonstrate that the steady-state tissue:plasma PCs for pyrethroids were inversely proportional to age. These differences become more pronounced as the age diminishes. At low exposure levels of DLM, ontogenic differences in plasma binding do not affect its brain uptake. However, increased brain entry of DLM in younger rats results from increased permeability of the BBB in these age groups.