The experimental Alzheimer drug phenserine: preclinical pharmacokinetics and pharmacodynamics

Abstract

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 of Alzheimer's disease (AD). Compared to physostigmine and tacrine, it is less toxic and robustly enhances cognition in animal models. To determine the time‐dependent effects of phenserine on cholinergic function, AChE activity, brain and plasma drug levels and brain extracellular acetylcholine (ACh) concentrations were measured in rats before and after phenserine administration. 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 rapidly 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‐life >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 bioavailability of 100%. Striatal, in vivo microdialysis in conscious, freely‐moving phenserine‐treated rats demonstrated >3‐fold rise in brain ACh levels. Phenserine thus is rapidly absorbed and cleared from the body, but produces a long‐lasting stimulation of brain cholinergic function at well tolerated doses and hence has superior properties as a drug candidate for AD. It selectively inhibits AChE, minimizing potential BChE side effects. Its long duration of action, coupled with its short pharmacokinetic half‐life, reduces dosing frequency, decreases body drug exposure and minimizes the dependence of drug action on the individual variations of drug metabolism commonly found in the elderly.

Selective butyrylcholinesterase inhibition elevates brain acetylcholine, augments learning and lowers Alzheimer β-amyloid peptide in rodent

“…in rodents do not result in classical cholinergic toxicity, with no evidence of tremor, increased salivation, or lacrimation as found with high doses of selective AChE inhibitors (20). By comparison, the selective AChE inhibitor, phenserine, would be lethal at this dose (20). Therefore, cymserine and analogs appear to have a favorable pharmacological profile.…”

“…for enzyme inhibition studies. Brain and plasma drug levels were determined by high-pressure liquid chromatography as described for phenserine (20). Plasma, brain, or cerebrospinal fluid (CSF) levels of ChE inhibition were determined as described (20).…”

“…Log octanol͞water partition coefficients for cymserine and analogs were calculated for lipophilicity assessment (20).…”

“…or vehicle (n ϭ 4 per group) in a manner similar to animals undergoing microdialysis. They were killed 40 min thereafter, parietal cerebral cortex was removed, and levels of AChE and BChE activity were determined (20).…”

Preclinical Investigation of the Topical Administration of Phenserine: Transdermal Flux, Cholinesterase Inhibition, and Cognitive Efficacy

“…of 337.4 and is lipophilic, with a log P value of 2.2. It has a high brain penetration (brain/plasma ratio of 10:1), a moderately long duration of action in rodents (half-life, t 1/2 of 8.25 h), and a preferential selectivity for AChE versus butyrylcholinesterase (BChE) of approximately 70-fold (Greig et al, 2000). Such characteristics have been purported to make ChE-Is more tolerable in humans (Greig et al, 1995(Greig et al, , 2005b, and furthermore, they make PS suitable for transdermal administration.…”