Purification and characterization of a human liver cocaine carboxylesterase that catalyzes the production of benzoylecgonine and the formation of cocaethylene from alcohol and cocaine.

Advances in molecular biology describing important enzyme systems involved in drug conjugation and deconjugation reactions and recent work indicating the importance of drug and xenobiotic conjugates as transport forms of biologically active compounds are reviewed comprehensively. Part One describes molecular events associated with the expression and regulation of transferases and hydrolases involved in Phase II drug conjugation and deconjugation. Part Two deals with the regulation of Phase II conjugation, and Part Three reviews critically the importance of drug conjugates in pharmacology and toxicology. This volume is an up-to-date source of information on this topic and will be of broad interest to pharmacologists and toxicologists.

Conjugation-deconjugation reactions in drug metabolism and toxicity.

Cocaine-induced myocardial ischemia and infarction: pathophysiology, recognition, and management.

The detection of a drug in a urine sample is usually a sound analytical procedure. However, pharmacologists and toxicologiest continue to uncover new and interesting circumstances that may influence the analytical results, or more likely, its interpretation. Future studies are needed to elucidate the pharmacological actions of drugs of abuse, both in the clinical overdose situation and upon workplace performance, and to define pharmacokinetic variables that influence the disposition of these drugs in the body and in the analytical specimen.

Testing for drugs of abuse. Pharmacokinetic considerations for cocaine in urine.

Simultaneous assay of cocaine, heroin and metabolites in hair, plasma, saliva and urine by gas chromatography—mass spectrometry

The enzyme-mediated transesterification of the 2-carboxymethyl ester of cocaine to a 2-carboxyethyl ester in the presence of ethanol has been characterized in mice by using both in vitro and in vivo systems. Hepatic subcellular fractionation of mouse livers demonstrated that cocaine transesterification activity was detectable only in the microsomal fraction. The in vitro microsomal transesterification of cocaine in the presence of ethanol was inhibited by fluoride and diisopropylfluorophosphate but was insensitive to physostigmine, thereby indicating that the reaction is specifically catalyzed by a carboxylesterase. The transesterification activity of hepatic microsomes showed saturable Michaelis-Menten kinetics in the presence of increasing concentrations of ethanol or cocaine. Cocaine transesterification specific activity in isolated mouse kidney microsomes was approximately 1.5-fold greater than that measured in the liver, suggesting that the kidney could play a significant role in ethyl ester formation. Collectively, these observations demonstrate that the transesterification of cocaine in the presence of ethanol is probably the result of hepatic and possibly renal carboxylesterases localized in the endoplasmic reticulum. The ethyl ester of cocaine was also detected in the livers of mice coadministered ethanol (3.0 g/kg intragastrically) and cocaine (50 mg/kg i.p.). Cocaine and cocaine ethyl ester displayed similar pharmacokinetic profiles, with hepatic half-lives of approximately 6.5 min. Pretreatment of the mice with 100 mg/kg tri-o-tolylphosphate completely blocked in vivo formation of the ethyl ester metabolite, further supporting the involvement of B-esterases in the transesterification of cocaine to cocaine ethyl ester.

C S Boyer

Papers

Enzymatic basis for the transesterification of cocaine in the presence of ethanol: evidence for the participation of microsomal carboxylesterases.