Distribution of tacrine across the blood-brain barrier in awake, freely moving rats using in vivo microdialysis sampling.

Microdialysis was used to sample simultaneously the distribution of THA (9-amino-1,2,3,4-tetrahydroacridine; Tacrine), a potential anti-Alzheimer agent, both in blood and across the blood-brain barrier of anesthetized and awake, freely moving rats. Microdialysis probes were implanted in the jugular vein and dorsal hippocampus and dialysis samples were simultaneously collected from both sites. Dialysis samples were analyzed using a microbore column chromatographic assay with a detection limit of 0.3 ng/ml. Pharmacokinetic parameters were calculated after a 1 mg/kg intravenous dose of THA. Plasma pharmacokinetics followed a biexponential mode, with t1/2(dis.) = 8.4 +/- 2.7 min and t1/2(elim.) = 76.7 +/- 24.2 min for awake, freely moving rats. THA rapidly penetrated the blood-brain barrier, with maximum concentrations attained within 60 min post-dose. In the brain of awake, freely moving rats t1/2(abs.) was 26.0 +/- 5.2 min and t1/2(elim.) was 99.1 +/- 17.7 min. THA levels in hippocampus extracellular fluid were 10 times lower than those in plasma. For anesthetized rats, the t1/2(elim.) in blood was 154.8 +/- 46.8 min, while in the hippocampus t1/2(elim.) was 159.5 +/- 31.7 min. The binding of THA in rat plasma was 56.2 +/- 5.0%, while the fraction bound to rat whole blood was 73.3 +/- 4.1% as determined by microdialysis and ultrafiltration.