Pharmacokinetics and pharmacodynamics of the acetylcholinesterase inhibitor 2,2,2-trifluoro-1-(3-trimethylsilylphenyl) ethanone in dog. Potential for transdermal patch delivery.

MDL 73,745 (2,2,2-trifluoro-1-(3-trimethylsilylphenyl) ethanone, CAS 132236(18-1) is a novel tight-binding inhibitor of acetylcholinesterase (AChE), which is in development as a potential therapeutic compound in the symptomatic treatment of Alzheimer's disease. Pharmacokinetics and pharmacodynamics of the compound were studied in the dog after single intravenous (i.v. 2 mg/kg), oral p.o. 10 mg/kg) and sub-cutaneous (s.c., 10 mg/kg) administrations of [14C]-MDL 73,745. Plasma concentrations of total radioactivity were much higher than those of parent drug after i.v., p.o. and s.c. administration, indicating extensive metabolism of the compound, although this was less after, s.c. administration than after p.o. administration. The bioavailability (F) was 34% after s.c. administration, compared with 4% after p.o. administration. The low bioavailability after p.o. administration was not due to poor drug absorption, as over 64% of the dose was absorbed. Pharmacokinetic parameters, calculated after i.v. administration, showed a terminal elimination half-life of 24 h, total body plasma clearance of around 70 ml/min/kg and apparent volume of distribution of 150 l/kg. AChE activity was almost 100% inhibited after i.v. administration, and over 80% inhibited 1 h after p.o. administration. In both cases, AChE activity returned to baseline levels by 12 h. AChE was around 80% inhibited 4 h after s.c. administration, and did not return to baseline levels until 36 h after drug administration. A combined pharmacokinetic-pharmacodynamic (PK-PD) effect model demonstrated that the extent of AChE inhibition could be correlated with plasma levels of the parent compound. As s.c. administration increased F, and led to longer AChE inhibition, transdermal (t.d.) delivery was assessed in the same animals. Patches, corresponding to a dose of 50 mg/kg, were applied to the shaved lateral abdominal skin for a period of 96 h. Sustained plasma concentrations of the parent drug were observed over the 96 h period of t.d. application. Mean (+/- SD) maximum plasma concentrations (Cmax) of 26.9 +/- 4.3 ng/ml were found 3.7 +/- 2.5 h after t.d. patch application und F was around 13%. AChE inhibition reached a maximum of 72% at 6 h after t.d. application and was still 35% at 96 h. The rate of release from the delivery system, per unit surface area, (ko) was calculated to be 7.7 micrograms/cm2. Transdermal delivery of MDL 73,745 thus decreased the important hepatic first-pass effect, and led to sustained plasma concentrations of drug, thus avoiding peaks and troughs which could lead to side-effects or poor efficacy.