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

Abstract 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.