In vitro competitive inhibition of plasma cholinesterase by cocaine: normal and variant genotypes

To determine the inhibitory constant, Ki, of cocaine for a number of the different genetic variants of human plasma cholinesterase.

In vitro analysis of plasma cholinesterase activity in the presence of cocaine as a competitive inhibitor.

Six normal (UU) control sera and seven sera with the following plasma cholinesterase genotypes were assayed: AA, UA, AS, UF, US, AF and SS. Plasma cholinesterase activity was determined in the samples by colorimetric measurement of propionylthiocholine metabolism over a range of concentrations. Competitive activities were then determined in the presence of varying concentrations of cocaine. Double reciprocal plots (1/v vs 1/S) were used to calculate Km and Vmax for propionylthiocholine, and Ki for cocaine for each genotype.

The variant forms of the plasma cholinesterase had high cocaine Ki values--all were approximately ten times greater than the Ki for normal plasma cholinesterase.

Since the inhibitory constant is an indirect measure of an enzyme's affinity for a competing substrate, a high Ki for cocaine at recreational or therapeutic concentrations would translate into a longer in vivo half-life. Our results support the growing evidence that low plasma cholinesterase activity predisposes to cocaine toxicity.