Brain uptake, pharmacokinetics, and tissue distribution in the rat of neurotoxic N-butylbenzenesulfonamide

Abstract

The pharmacokinetics, cerebrovascular permeability, and tissue distribution of the neurotoxic plasticizer N-butylbenzenesulfonamide (NBBS) were determined in rats. A stable isotope-labeled form ([13C6]NBBS) was used to circumvent ubiquitous contamination that was evident whenever the native form was measured. Plasticizer decline in plasma, following an iv dose of 1 mg/kg, was described by a triexponential decay function. NBBS was cleared from plasma at a rate of 25 ml/min/kg, and 24 h after administration, plasma concentrations represented 0.04% of the administered dose. These data suggest rapid elimination and uptake into tissue; however, NBBS was not accumulated by any of the tissues studied (i.e., liver, kidney, muscle, adipose tissue, and brain). Given the critical interest in NBBS neurotoxicity, the brain uptake of [13C6]NBBS was further explored in experiments using the in situ brain perfusion technique. During perfusion with proteinfree saline for 15-30 s, the single-pass brain extraction for free [13C6]NBBS was very high (73-100%) with a unidirectional bloodbrain barrier transfer constant (Kin) of > 0.08 ml/s/g. No significant differences were found in [13C6]NBBS content among the measured brain regions. Plasma protein binding (70%) only slightly lowered the single-pass brain extraction to 48%. In summary, the results demonstrate that NBBS distributes rapidly to tissues, including brain. Though highly lipophilic with a Log octanol/water partition coefficient of 2.17 ± 0.09, brain:blood ratios (2:1) for NBBS were consistent throughout the experimental duration, with little indication of accumulation. © The Author 2007. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved.