Oral administration of heptylphysostigmine in healthy volunteers: a preliminary study

Heptylphysostigmine (HP) is a reversible cholinesterase (ChE) inhibitor with greater lipophilicity and longer inhibitory action than the parent compound, physostigmine (Phy). Single (0.1-0.6 mg/kg) and multiple 5-day (0.1-0.3 mg/kg) doses of HP were administered to 21 young normal volunteers. The relationship between logarithmic dose (mg/kg) and peak inhibition of red blood cell (RBC) ChE was linear with dose. In one subject given 0.6 mg/kg of HP, concentration in plasma was 0.68 ng/ml at 2 h and gradually declined to below the detection limit by 4 h. Peak plasma and RBC ChE inhibitions of 31.2% and 55.8% were achieved at 2 h for both with a 0.6 mg/kg dose. Chronic studies did not result in any accumulation of ChE inhibition up to 0.2 mg/kg b.i.d., whereas at 0.3 mg/kg b.i.d. 10-15% RBC ChE inhibition was maintained. Higher levels of ChE inhibition can be achieved with HP than with its parent compound, Phy. Red blood cell ChE inhibition recovered more slowly than plasma even though the maximum inhibition was similar for both enzymes.