ACETYLCHOLINESTERASE INHIBITION BY ZIFROSILONE - PHARMACOKINETICS ANDPHARMACODYNAMICS

Objective: To determine the pharmacokinetics, pharmacodynamics and saf ety of the acetylcholinesterase inhibitor zifrosilone in healthy male volunteers. Methods: Pharmacokinetics, pharmacodynamics, and tolerance of zifrosilone were studied in a double-blind, sequential, single-esc alating-dose, randomized panel design. Each panel consisted of six sub jects, with four subjects receiving zifrosilone (10, 30, 60, 90, 120, 150, 200, 250, and 300 mg orally) and two subjects receiving matching placebo. Serial blood samples were obtained for zifrosilone plasma con centrations and red blood cell acetylcholinesterase and butyrylcholine sterase activities. Participating subjects (n = 54) were men between t he ages of 18 and 45 years, Each subject had a normal physical examina tion, electrocardiogram, serum chemistries, hematology, urinalysis, an d test for human immunodeficiency virus at screening. Results: A great er than proportionate increase in mean plasma concentration values for area under the curve from time zero to infinity was observed over the 200 to 300 mg dose range groups. Red blood cell acetylcholinesterase showed a dose-inhibition relationship, with a mean maximum inhibition of 20.9% at 10 mg that increased to 62.1% at 300 mg. Butyrylcholineste rase activity was relatively unaffected by zifrosilone (<20% inhibitio n at 300 mg). For doses greater than or equal to 200 mg, an E(max) pha rmacodynamic model was used to describe the relationship between zifro silone plasma concentration and red blood cell acetylcholinesterase in hibition (E(max) = 83.8%; EC(50) = 0.65 ng/ml). Conclusions: Zifrosilo ne showed dose-dependent pharmacokinetics after oral administration an d was effective in causing selective inhibition of red blood cell acet ylcholinesterase.