The experimental alzheimer drug phenserine: Preclinical pharmacokinetics and pharmacodynamics

N. H. Greig, E. De Micheli, H. W. Holloway, Q. S. Yu, T. Utsuki, T. A. Perry, D. K. Ingram, J. Deutsch, Debomoy Lahiri, T. T. Soncrant

Research output: Contribution to journalArticle

57 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)74-84
Number of pages11
JournalActa Neurologica Scandinavica, Supplement
Volume102
Issue number176
StatePublished - 2000

Fingerprint

Pharmacokinetics
Physostigmine
Brain
Butyrylcholinesterase
Tacrine
Pharmaceutical Preparations
Cholinergic Agents
Acetylcholine
Half-Life
Alzheimer Disease
Phenylcarbamates
Corpus Striatum
Maximum Tolerated Dose
Poisons
Cholinesterase Inhibitors
Microdialysis
Acetylcholinesterase
Cognition
Biological Availability
Substance-Related Disorders

Keywords

  • Acetylcholine
  • Acetylcholinesteras e
  • Alzheimer's disease
  • Anticholinesterases
  • Butyrylcholinesterase
  • Cholinomimetics
  • In vivo microdialysis

ASJC Scopus subject areas

  • Clinical Neurology
  • Neuroscience(all)

Cite this

Greig, N. H., De Micheli, E., Holloway, H. W., Yu, Q. S., Utsuki, T., Perry, T. A., ... Soncrant, T. T. (2000). The experimental alzheimer drug phenserine: Preclinical pharmacokinetics and pharmacodynamics. Acta Neurologica Scandinavica, Supplement, 102(176), 74-84.

The experimental alzheimer drug phenserine : Preclinical pharmacokinetics and pharmacodynamics. / Greig, N. H.; De Micheli, E.; Holloway, H. W.; Yu, Q. S.; Utsuki, T.; Perry, T. A.; Ingram, D. K.; Deutsch, J.; Lahiri, Debomoy; Soncrant, T. T.

In: Acta Neurologica Scandinavica, Supplement, Vol. 102, No. 176, 2000, p. 74-84.

Research output: Contribution to journalArticle

Greig, NH, De Micheli, E, Holloway, HW, Yu, QS, Utsuki, T, Perry, TA, Ingram, DK, Deutsch, J, Lahiri, D & Soncrant, TT 2000, 'The experimental alzheimer drug phenserine: Preclinical pharmacokinetics and pharmacodynamics', Acta Neurologica Scandinavica, Supplement, vol. 102, no. 176, pp. 74-84.
Greig NH, De Micheli E, Holloway HW, Yu QS, Utsuki T, Perry TA et al. The experimental alzheimer drug phenserine: Preclinical pharmacokinetics and pharmacodynamics. Acta Neurologica Scandinavica, Supplement. 2000;102(176):74-84.
Greig, N. H. ; De Micheli, E. ; Holloway, H. W. ; Yu, Q. S. ; Utsuki, T. ; Perry, T. A. ; Ingram, D. K. ; Deutsch, J. ; Lahiri, Debomoy ; Soncrant, T. T. / The experimental alzheimer drug phenserine : Preclinical pharmacokinetics and pharmacodynamics. In: Acta Neurologica Scandinavica, Supplement. 2000 ; Vol. 102, No. 176. pp. 74-84.
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