Prospective of human butyrylcholinesterase as a detoxifying antidote and potential regulator of controlled-release drugs

Abstract

Butyrylcholinesterase from human plasma (HuBChE) is a potential drug candidate that can be employed in several therapeutic fields. This is attributed to the unique structure of the enzyme that allows selective accommodation of a variety of substrates and inhibitors, some of which are excluded from the catalytic gorge of acetylcholinesterase. Enhancement of endogenous levels of HuBChE can protect against the toxicity of organophosphate pesticides and nerve agents, reduce risks of complications due to cocaine abuse, reverse muscle relaxant-induced apnea following surgery anesthesia, and alleviate symptoms caused by local anesthetics. It can be used either prophylactically or as a treatment drug. Treatment with HuBChE offers replacement therapy of traditional pharmacological antidotes that suffer from several disadvantages. In addition, endogenous HuBChE is capable of biotransformation of ester- or carbamate-bond containing prodrugs to active therapeutic molecules, and has the potential of improvement of bioavailability and safety of numerous drugs with sales records. In certain cases HuBChE may be administered before, with, or after the prodrug. HuBChE is absorbed in high yield from muscles and its circulatory stability is sufficient to provide significant therapeutic levels for several days, even after a single dose load. Based on limited studies with partially purified HuBChE, the enzyme seems to lack significant physiological incompatibilities in humans that may prevent its use as a drug. Clinical trials aimed at providing pharmacokinetic data and evaluation of safety issues of acute and chronic administration of purified HuBChE are expected to advance the concept of using the enzyme as a multipurpose drug. Drug Dev. Res. 50:298–308, 2000. © 2000 Wiley-Liss, Inc.