Pharmacokinetic and Pharmacodynamic Analysis of Acetylcholinesterase Inhibition by Distigmine Bromide in Rats

Abstract

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.

Distigmine Bromide Produces Sustained Potentiation of Guinea-Pig Urinary Bladder Motility by Inhibiting Cholinesterase Activity

“…5A, 6). Since brain AChE activity was not inhibited by distigmine, 22) its pharmacological actions are presumed to be mediated by effects on peripheral AChE. Therefore, the present findings and previous reports indicate that the observed sustained effects of distigmine on urinary bladder motility reflect its inhibition of bladder tissue AChE.…”

“…The collected bloods were treated with heparin and then used for the analysis of blood AChE activity. Blood AChE activity was determined as described previously, 21,22) with minor modifications. First, the whole blood samples (5 µL) were incubated for 10 min at 37°C in a solution containing 2985 µL phosphate buffer (0.1 M, pH=7.4), 10 µL tetraisopropyl pyrophosphoramide (iso-OMPA; a selective butyrylcholinesterase (BChE) inhibitor; 3×10 −4 M), 23) and 100 µL 5,5′-dithiobis(2-nitrobenzoic acid) (DTNB; 10 −2 M).…”

“…Ito et al also reported that rat erythrocyte AChE inhibition by distigmine did not correlate with the plasma concentrations of this drug following oral administration. 22) The possibility that active metabolites of distigmine generated by hepatic metabolism contribute to these pharmacodynamic effects cannot be completely ruled out at present, although this seems unlikely because: 1) distigmine was reported to be excreted by the kidneys 24) using 14 C-labeled distigmine; 2) three chemical candidates that are predicted to be generated by decomposition of distigmine did not affect AChE activity 25) ; 3) distigmine-mediated enhancement of AChinduced contraction of guinea pig urinary bladder smooth muscle lasted for ≥12 h after washing out with distigmine-free solution 25) ; and 4) distigmine inhibited recombinant human AChE activities for >48 h after the separation of distigmine from the enzyme by centrifugation (our unpublished observation). One possible explanation for this discrepancy would thus be the retention of distigmine within urinary bladder tissues or a robust binding to AChE, which would sequester the compound at its site of action.…”

Effects of Distigmine on the Mechanical Activity of Urinary Bladder Smooth Muscle

“…During urination, ACh and ATP are released from the parasympathetic nerve ending in the UB in response to nerve excitation. [30][31][32][33][34][35][36] Distigmine inhibits acetylcholinesterase (AChE) activity in the UB. 37,38) Therefore, it is presumed that distigmine enhances the contractile force of the UBSM by increasing ACh concentration in the synaptic cleft between the parasympathetic nerve ending and the UBSM.…”

The Long-Lasting Enhancing Effect of Distigmine on Acetylcholine-Induced Contraction of Guinea Pig Detrusor Smooth Muscle Correlates with Its Anticholinesterase Activity

“…12) In clinical use, a myasthenia gravis patient who received an oral administration of distigmine exhibited symptomatic relief for 36 h, 1) while the half-time for AChE inhibition recovery in red blood cells after distigmine administration was estimated to be approximately 40 h. 13) However, the duration of distigmine's effect on UB motility remains unclear. We have recently attempted to clarify this question in relation to the blood concentration of distigmine in guinea pigs and determined that an intravenous bolus injection of distigmine maintained an increased maximal intravesical pressure for 12 h after injection and that this effect persisted even after the elimination of distigmine from the blood.…”