The experimental Alzheimer drug phenserine: preclinical pharmacokinetics and pharmacodynamics

Phenserine. a phenylcarbamate of physostigmine, is a new potent and highly selective acetylcholinesterase (AChE) inhibitor, with a > 50-fold activity versus butyrylcholinesterase (BChE), in clinical trials for the treatment o f Alzheimer's disease (AD). Compared to physostigmine and tacrine, it is le ss toxic and robustly enhances cognition in animal models. To determine the time-dependent effects of phenserine on cholinergic function, AChE activit y, brain and plasma drug levels and brain extracellular acetylcholine (ACh) concentrations were measured in rats before and after phenserine administr ation. Additionally, its maximum tolerated dose, compared to physostigmine and tacrine, was determined. Following i.v. dosing, brain drug levels were 10-fold higher than those achieved in plasma, peaked within 5 min and rapid ly declined with half-lives of 8.5 and 12.6 min, respectively. In contrast, a high (,70%;,) and long-lasting inhibition of AChE was achieved (half-lif e > 8.25 h). A comparison between the time-dependent plasma AChE inhibition achieved after similar oral and i.v. doses provided an estimate of oral bi oavailability of 100%. Striatal, in vivo microdialysis in conscious, freely -moving phenserine-treated rats demonstrated >3-fold rise in brain ACh leve ls. Phenserine thus is rapidly absorbed and cleared from the body, but prod uces a long-lasting stimulation of brain cholinergic function at well toler ated doses and hence has superior properties as a drug candidate for AD. It selectively inhibits AChE, minimizing potential BChE side effects. Its lon g duration of action, coupled with its short pharmacokinetic half-lift, red uces dosing frequency, decreases body drug exposure and minimizes the depen dence of drug action on the individual variations of drug metabolism common ly found in the elderly.