Chemistry and Metabolism

An ester of benzoic acid and the amino alcohol methylecgonine, Cocaine (methylbenzoylecgonine) contains atropine moiety and is chemically, but not pharmacologically, related to atropine. Cocaine is structurally different from other local anesthetics by virtue of its tropine moiety. However like other local anesthetics, cocaine consists of a hydrophobic and hydrophilic region. The hydrophobic region contains a benzene ring while the hydrophilic region consists of a secondary or tertiary amine. Cocaine is also similar to other local anesthetics due to its ester linkages, rendering it susceptible to hydrolysis in vitro and in vivo.

This drug is metabolized primarily to benzoylecgonine and ecgonine methyl ester by different mechanisms (Figure 12-1). It has conventionally been believed that the alkyl ester of cocaine is hydrolyzed to benzoylecgonine via spontaneous hydrolysis, and the phenyl ester of cocaine is hydrolyzed to ecgonine methyl ester via plasma esterase. However, studies have revealed that this is more multifaceted than initially thought, as liver esterase are involved in these metabolic pathways as well. Both benzoylecgonine and ecgonine methyl ester are further hydrolyzed to ecgonine through pH and temperature-dependant chemical hydrolysis, although this process occurs much faster for ecgonine methyl ester than for benzoylecgonine.

Ecgonine is known to surpass benzoylecgonine concentrations in urine in certain situations. In 104 of 139 urine specimens where ecgonine was present at or above 50ng/mL, the average ecgonine concentration was just about 5 times the comparable benzoylecgonine concentration. Based on the benzoylecgonine concentrations, this scenario appears to be most likely during the late stages of urinary excretion of a dose of cocaine. However, pharmacokinetic studies measuring this metabolite have not yet been performed, and its occurrence may be a result of hydrolysis of benzoylecgonine and/or ecgonine methyl ester.

In urine workplace drug-testing settings, benzoylecgonine is the most general analyte tested to detect prior cocaine use. It is currently the only analyte that may be tested in US federally regulated drug tests for cocaine. However in non-regulated testing, and testing in other matrices the parent drug as well as some other metabolites may be included as part of the testing protocol.

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