Benzoic acid is not the only important product of accelerated metabolism of cocaine

Abstract

Xiabin Chen et al.(1) describe pioneering work with a modified drug-metabolizing enzyme, a butyrylcholinesterase (BChE) analog, intended to prolong BChE activity in humans, hoping that the result would be accelerated cocaine metabolism. This work is exciting to those involved in pharmacokinetic approaches to drug toxicity; such constructs promise to be the first drug-metabolizing enzymes used as therapeutic agents. The analog described (1) seems to be the third of its type; this analog is apparently the longest lasting in the series (2, 3).Cocaine is metabolized three ways: (i) BChE, in blood, hydrolyzes the benzoate link producing ecgonine methyl ester (EME); (ii) carbonyl esterase, in the liver, hydrolyzes the other ester link, producing benzoyl ecgonine (BE); and (iii) oxidative enzymes in the liver remove the N-methyl group producing norcocaine (NC) (4). These initial products are further metabolized, in particular EME to ecgonine and NC to norcocaine methyl ester. Benzoic acid (BA) can be formed from both EME and NC. Chen et al. (1) assayed BA as the sole indicator of metabolite formation. EME has been considered to be inactive, especially because it lacks the properties of cocaine; NC shares at least some of those properties. Measurement of BA by Chen et al. (1), although demonstrating that cocaine metabolism occurred, failed to differentiate between initial metabolites with significant differences in properties. Other work has shown that the shorter-acting analogs of BChE preferentially convert cocaine to EME (2, 3). EME is not inactive (5). It crosses the blood-brain barrier and can reverse effects of scopolamine, a CNSactive antimuscarinic compound with related chemistry. It can improve cognition in aged rats, at the same time showing anxiolytic activity. EME can alleviate inhibition by cocaine at a novel regulatory site on nicotinic acetylcholine receptors; this site is implicated in adverse effects of cocaine (6). Furthermore, EME blocks the convulsion-inducing effect of cocaine (7), providing an example of a drug metabolite pharmacologically reversing the effect of its precursor. Thus, at least two of the modified hydrolases (2, 3) pioneer novel drug metabolism technology by creation of significant concentrations of a metabolic product with novel pharmacological mechanisms.Chen et al.(1) leave unanswered the question of whether their enzyme initially catalyzes EME formation. EME, BE, and NC could have been assayed individually. Chen et al. do not tell us whether EME concentrations were raised in their experiments, and thus whether there might be a component of pharmacological alleviation of the effects of cocaine by EME in the action of the enzyme, in contrast to the probable properties of RBP-8000 (2) and TV-1380 (3), which significantly increase the concentrations of EME in plasma. We look forward to reports of future experiments that clarify the route to benzoic acid with this enzyme, and to learning whether this approach uses EME as a product of acceleration of the metabolism of cocaine or as a p...

Evaluation of Cocaine Effect on Endogenous Metabolites of HepG2 Cells Using Targeted Metabolomics

“…Benzoic acid was found to strongly augment in the treated cells while it had also a gradual increase at three time points since it is involved in the cocaine’s hepatic metabolism and can be formed by both EME and norcocaine [ 37 ].…”