TY - JOUR
T1 - Acetylcholinesterase inhibition by zifrosilone
T2 - Pharmacokinetics and pharmacodynamics
AU - Cutler, Neal R.
AU - Seifert, Randall D.
AU - Schleman, Margo M.
AU - Sramek, John J.
AU - Szylleyko, Olo J.
AU - Howard, Danny R.
AU - Barchowsky, Aaron
AU - Wardle, Thomas S.
AU - Brass, Eric P.
PY - 1995/7
Y1 - 1995/7
N2 - Objective: To determine the pharmacokinetics, pharmacodynamics and safety of the acetylcholinesterase inhibitor zifrosilone in healthy male volunteers. Methods: Pharmacokinetics, pharmacodynamics, and tolerance of zifrosilone were studied in a double-blind, sequential, single-escalating-dose, randomized panel design. Each panel consisted of six subjects, 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 concentrations and red blood cell acetylcholinesterase and butyrylcholinesterase activities. Participating subjects (n = 54) were men between the ages of 18 and 45 years. Each subject had a normal physical examination, electrocardiogram, serum chemistries, hematology, urinalysis, and test for human immunodeficiency virus at screening. Results: A greater 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. Butyrylcholinesterase activity was relatively unaffected by zifrosilone (<20% inhibition at 300 mg). For doses ≥ 200 mg, an E(max) pharmacodynamic model was used to describe the relationship between zifrosilone plasma concentration and red blood cell acetylcholinesterase inhibition (E(max) = 83.8%; EC50 = 0.65 ng/ml). Conclusions: Zifrosilone showed dose-dependent pharmacokinetics after oral administration and was effective in causing selective inhibition of red blood cell acetylcholinesterase.
AB - Objective: To determine the pharmacokinetics, pharmacodynamics and safety of the acetylcholinesterase inhibitor zifrosilone in healthy male volunteers. Methods: Pharmacokinetics, pharmacodynamics, and tolerance of zifrosilone were studied in a double-blind, sequential, single-escalating-dose, randomized panel design. Each panel consisted of six subjects, 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 concentrations and red blood cell acetylcholinesterase and butyrylcholinesterase activities. Participating subjects (n = 54) were men between the ages of 18 and 45 years. Each subject had a normal physical examination, electrocardiogram, serum chemistries, hematology, urinalysis, and test for human immunodeficiency virus at screening. Results: A greater 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. Butyrylcholinesterase activity was relatively unaffected by zifrosilone (<20% inhibition at 300 mg). For doses ≥ 200 mg, an E(max) pharmacodynamic model was used to describe the relationship between zifrosilone plasma concentration and red blood cell acetylcholinesterase inhibition (E(max) = 83.8%; EC50 = 0.65 ng/ml). Conclusions: Zifrosilone showed dose-dependent pharmacokinetics after oral administration and was effective in causing selective inhibition of red blood cell acetylcholinesterase.
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U2 - 10.1016/0009-9236(95)90072-1
DO - 10.1016/0009-9236(95)90072-1
M3 - Article
C2 - 7628183
AN - SCOPUS:0029092388
SN - 0009-9236
VL - 58
SP - 54
EP - 61
JO - Clinical pharmacology and therapeutics
JF - Clinical pharmacology and therapeutics
IS - 1
ER -