ToxSci Advance Access originally published online on March 15, 2007
Toxicological Sciences 2007 97(2):253-264; doi:10.1093/toxsci/kfm057
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Brain Uptake, Pharmacokinetics, and Tissue Distribution in the Rat of Neurotoxic N-Butylbenzenesulfonamide
* Bioanalytical Mass Spectrometry Facility, M305 Wallace Wurth Building, University of New South Wales, Sydney, NSW 2052, Australia
Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, 1300 Coulter Boulevard, Amarillo, Texas 79106
Department of Pediatrics and Division of Endocrinology, Metabolism and Diabetes, School of Medicine, University of Colorado Health Sciences Center, Mail Stop 8119 PO Box 6611, Aurora, Colorado 80045
1 To whom correspondence should be addressed. E-mail: netnoggy{at}netscape.net.
Received February 14, 2007; accepted March 5, 2007
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Abstract |
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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 protein-free saline for 15–30 s, the single-pass brain extraction for free [13C6]NBBS was very high (73–100%) with a unidirectional blood-brain 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.
Key Words: N-butylbenzenesulfonamide; neurotoxin; plasticizer; cerebrovascular; permeability; blood-brain barrier.