Esters

Several examples of hydrolysis of esters, lactones, and amides are discussed elsewhere in this Volume (see 5.44 Prodrug Objectives and Design). To complement this, we present here a few examples of (active) drugs whose metabolism is catalyzed to a large extent by hydrolases and which serve to illustrate some important concepts.

( — )-Cocaine (1, Figure 2) has led to unexpected insights into relations between metabolism and molecular toxicology (reviewed in5). This xenobiotic is metabolized by various routes including N-demethylation (to form norcocaine), N-oxygenation, aromatic hydroxylation, and hydrolysis of its two ester groups. The latter route is particularly important since it is globally a route of detoxification that accounts for as much as 90% of the dose in humans, who excrete high urinary concentrations of benzoylecgonine (2), ecgonine methyl ester (3), and ecgonine (4).

Studies using human serum and liver showed enzymatic hydrolysis of the benzoyl ester bridge, whereas the hydrolysis of the methyl ester group occurs both nonenzymatically and enzymatically. Furthermore, marked tissue differences in the formation of benzoylecgonine from cocaine were seen in the rat, with more than one enzyme activity being involved. Three human enzymes are now known to be involved in the hydrolysis of cocaine. One is a liver carboxylesterase (designated hCE-1), which catalyzes the hydrolysis of the methyl ester group. As for the benzoyl ester goup, it is hydrolyzed by the liver carboxylesterase hCE-2 and serum cholinesterase. Natural ( — )-(2R;3S)-cocaine (1) is a relatively poor substrate of hepatic carboxylesterases and plasma cholinesterase (EC 3.1.1.8), and also a potent competitive inhibitor of the latter enzyme. In contrast, its unnatural enantiomer (+ )-(2S;3R)-cocaine is a good substrate of carboxylesterases and cholinesterase. Because hydrolysis is a route of detoxification for cocaine and its stereoisomers, such metabolic differences have a major impact on their monooxygenase-catalyzed toxification, a reaction of particular effectiveness for ( — )-cocaine.

There is an additional factor that contributes to the toxicity of cocaine, namely its interaction with ethanol.13,14 Many cocaine abusers simultaneously ingest ethanol probably to experience a potentiation of effects and a decrease in headaches. It is now known that ethanol interferes in two ways with the metabolism of cocaine, first by inhibiting its hydrolysis and second by allowing a transesterification to form benzoylecgonine ethyl ester (5, Figure 2). This reaction of transesterification is also catalyzed by hCE-1. The benzoylecgonine ethyl ester is commonly known as cocaethylene, and it is of clear significance since it retains the pharmacological and toxicological properties of cocaine, in particular its CNS and hepatic effects.

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