Pharmacokinetic and pharmacodynamic analysis of acetylcholinesterase inhibition by distigmine bromide in rats.
Distigmine bromide (distigmine) is associated with a serious adverse reaction, cholinergic crisis, due to a marked decrease in serum acetylcholinesterase (AChE) levels. Clarifying the relationship between the plasma concentration and the inhibitory effect on AChE of distigmine is thus important for the proper use of the drug. The plasma drug concentration and AChE activity in whole blood from rats were measured simultaneously 3 min to 12 h after the oral administration of distigmine at different doses, and the data were subjected to a pharmacokinetic/pharmacodynamic (PK/PD) analysis. Clockwise hysteresis was observed between the plasma concentration of distigmine and the time course of AChE inhibition. Distigmine also displayed a delayed and sustained inhibition of blood AChE activity. We then assumed an effect compartment for the relationship between the plasma concentration of distigmine and AChE inhibition and analyzed the time course of AChE activity using a sigmoid maximum inhibitory effect model as the pharmacodynamic model. In conclusion, there is a time lag between the plasma concentration and inhibitory effect of distigmine in rats, and such a relationship could be resolved with an effect compartment model. Thus, the inhibitory effect of distigmine on AChE could be predicted by the PK/PD analysis.
Ito
Yoshihiko
Y
Department of Pharmacokinetics and Pharmacodynamics, Global Center of Excellence (COE) and Clinical Pharmaceutics, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka, Japan.
Harada
Taketsugu
T
Fushimi
Kasumi
K
Kagawa
Yoshiyuki
Y
Oka
Hidenobu
H
Nakazawa
Hiroshi
H
Homma
Reiko
R
Kato
Yoshihisa
Y
Yamada
Shizuo
S
D000110:Acetylcholinesterase / Q000378:metabolism*; D000818:Animals; D002800:Cholinesterase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D058851:GPI-Linked Proteins; D007275:Injections, Intravenous; D008297:Male; D023421:Models, Animal; D008954:Models, Biological; D011726:Pyridinium Compounds / Q000008:administration & dosage / Q000097:blood* / Q000493:pharmacokinetics* / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D002800:Cholinesterase Inhibitors; D058851:GPI-Linked Proteins; D011726:Pyridinium Compounds; D000110:Acetylcholinesterase; C548246:Ache protein, rat; C084645:distigmine