ToxSci Advance Access published online on March 15, 2007
Toxicological Sciences, doi:10.1093/toxsci/kfm057
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Brain uptake, Pharmacokinetics and Tissue Distribution in the Rat of Neurotoxic N-butylbenzenesulfonamide
1 Bioanalytical Mass Spectrometry Facility, M305 Wallace Wurth Building, University of New South Wales (UNSW), Sydney, NSW 2052, Australia 2 Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, 1300 Coulter Boulevard, Amarillo, Texas 79106 USA 3 Department of Pediatrics and Division of Endocrinology, Metabolism & Diabetes, School of Medicine, University of Colorado Health Sciences Center, Mail Stop 8119 P.O. Box 6611, Aurora, Colorado, 80045 USA
* Author to whom correspondence should be addressed. email: netnoggy{at}netscape.net
Received February 14, 2007; revision 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 plasticiser 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. Plasticiser decline in plasma, following an intravenous 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 hours 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 (ie., 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; plasticiser; cerebrovascular; permeability; blood-brain barrier.