Brain uptake, pharmacokinetics, and tissue distribution in the rat of neurotoxic N-butylbenzenesulfonamide.
The pharmacokinetics, cerebrovascular permeability, and tissue distribution of the neurotoxic plasticizer N-butylbenzenesulfonamide (NBBS) were determined in rats. A stable isotope-labeled form ([(13)C(6)]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 [(13)C(6)]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 [(13)C(6)]NBBS was very high (73-100%) with a unidirectional blood-brain barrier transfer constant (K(in)) of > 0.08 ml/s/g. No significant differences were found in [(13)C(6)]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.
Kumar
Ganesh
G
Bioanalytical Mass Spectrometry Facility, M305 Wallace Wurth Building, University of New South Wales, Sydney, NSW, Australia. netnoggy@netscape.net
Smith
Quentin R
QR
Hokari
Mitsuhiko
M
Parepally
Jagan
J
Duncan
Mark W
MW
D000465:Algorithms; D000818:Animals; D001798:Blood Proteins / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000502:physiology; D001921:Brain / Q000378:metabolism*; D002490:Central Nervous System / Q000378:metabolism; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D008401:Gas Chromatography-Mass Spectrometry; D007275:Injections, Intravenous; D007553:Isotope Labeling; D008297:Male; D020258:Neurotoxicity Syndromes / Q000378:metabolism*; D010525:Peripheral Nerves / Q000378:metabolism; D010968:Plasticizers / Q000493:pharmacokinetics* / Q000633:toxicity*; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000378:metabolism; D013449:Sulfonamides / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity*; D014018:Tissue Distribution; D000096926:Benzenesulfonamides
D001798:Blood Proteins; D010968:Plasticizers; D013449:Sulfonamides; C065565:N-butylbenzenesulfonamide; D000096926:Benzenesulfonamides