Abstract

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 C_max values of 0.13, 0.33, and 0.43 μg/ml, respectively, T_max values of 5.0, 6.7, and 8.8 min, respectively, and t_1/2 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 C_max (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.