RT Journal Article
SR Electronic
T1 Pharmacokinetics of the Novel Nicotinic Receptor Antagonist <em>N</em>,<em>N</em>′-Dodecane-1,12-diyl-bis-3-picolinium Dibromide in the Rat
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 2024
OP 2029
DO 10.1124/dmd.108.020354
VO 36
IS 10
A1 Zaineb A. Fadhel Albayati
A1 Linda P. Dwoskin
A1 Peter A. Crooks
YR 2008
UL http://dmd.aspetjournals.org/content/36/10/2024.abstract
AB Plasma and brain concentrations of the nicotinic acetylcholine receptor antagonist and blood-brain barrier choline transporter substrate, N,N′-dodecane-1,12-diyl-bis-3-picolinium dibromide (bPiDDB), were analyzed by liquid β-scintillation spectrometry after administration of [14CH3]bPiDDB to male Sprague-Dawley rats. Plasma concentrations of [14CH3]bPiDDB were determined at 10 time points over 3 h. Absolute plasma bioavailabilities (1, 3, and 5.6 mg/kg s.c.) were 80.3, 68.2, and 103.7%, respectively. bPiDDB (1, 3, and 5.6 mg/kg) gave Cmax values of 0.13, 0.33, and 0.43 μg/ml, respectively, Tmax values of 5.0, 6.7, and 8.8 min, respectively, and t1/2 values of 76.0, 54.6, and 41.7 min, respectively. Mean area under the plasma concentration versus time curve from time zero to infinity (micrograms per minute per milliliter) and mean Cmax (μg/ml) values were dose-dependent (r2 = 0.9361 and 0.7968, respectively) over the dose range studied. No metabolism of [14CH3]bPiDDB was detected with any dose of bPiDDB administered. Only moderate protein binding (63–65% in plasma and 59–62% in brain supernatant) was observed, which was reversible. Brain concentrations and brain/plasma ratios of bPiDDB after a single 5.6 mg/kg s.c. dose over 5 to 60 min ranged from 0.09 to 0.33 μg/g brain tissue and were maximal at 10 min after injection, representing approximately 0.6% of the administered dose. Brain/blood ratio (0.18 at 5 min to 0.51 at 60 min after injection) was observed, indicating that clearance from brain is slower than clearance from plasma. The results show that bPiDDB is distributed rapidly from the site of injection into plasma, affords good plasma concentrations, and appears to reach brain tissues via facilitated transport by the blood-brain barrier choline transporter to afford therapeutically relevant concentrations in rat brain. The American Society for Pharmacology and Experimental Therapeutics