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 acetylcholinesteras e (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 clog after si ngle intravenous (iv 2 mg/kg), oral p.o. 10 mg/kg) and sub-cutaneous ( s.c., 10 mg/kg) administration of [C-14]-MDL 73, 745. Plasma concentra tions of total radioactivity, were much higher than those of parent dr ug after iv., p.o. and sc administration, indicating extensive metabol ism of the compound, although this was less after sc. administration t han 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 ads orption, as over 64% of the dose was absorbed. Pharmacokinetic paramet ers calculated after iv 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 alm ost 100% inhibited after iv ad ministration, and over 80% inhibited 1 h after p.o. administration In both cases, AChE activity returned to b ase-line levels by 12 h. AChE was around 80% inhibited 4 h after sc ad ministration, and did not return to baseline levels until 36 h after d rug and administration. A combined pharmacokinetic-pharmacodynamic (PK -PD) effect model demonstrated that the extent of AChE inhibition coul d be correlated with plasma levels of the parent compound As sc. admin istration increased F and led to longer AChE inhibition, transdermal ( t.d) delivery was assessed in the same animals Patches corresponding t o a dose of 50 mg/kg, were applied to the shaved lateral abdominal ski n 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 (C-max) of 269 +/- 4.3 ng/ml were fo und 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 syst em, per unit surface area, (k(o)) was calculated to de 7.7 mu g/h/cm(2 ). Transdermal delivery of MDL 73,745 thus decreased the important hep atic first-pass effect, and led to sustained plasma concentrations of drug, thus avoiding peaks and troughs which could lead to side effects of poor efficacy.