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 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.
Laboratory of Neurosciences, Intramural Research Program, National Institute of Aging, Gerontology Research Center, Baltimore, MD 21224, USA. Greign@vax.grc.nia.nih.gov
N H
NH
Greig
E
E
De Micheli
H W
HW
Holloway
Q S
QS
Yu
T
T
Utsuki
T A
TA
Perry
A
A
Brossi
D K
DK
Ingram
J
J
Deutsch
D K
DK
Lahiri
T T
TT
Soncrant
D000284:Administration, Oral; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000473:pathology; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000502:physiology; D002800:Cholinesterase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D004195:Disease Models, Animal; D006207:Half-Life; D007262:Infusions, Intravenous; D008297:Male; D010830:Physostigmine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics* / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344; D013619:Tacrine / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology
D002800:Cholinesterase Inhibitors; D013619:Tacrine; D010830:Physostigmine; C092280:phenserine