Cocaine liver

However, there are some data on interactions of phosphate esters with other compounds. Cocaine undergoes metabolism by three major routes one of these routes involves hydrolysis by liver and plasma cholinesterases to form ecgonine methyl ester. It has been suggested that cocaine users with serious complications tend to have lower plasma cholinesterase levels. Thus, it is possible that individuals with decreased plasma cholinesterase levels (such as resulting from organophosphate ester exposure) may be highly sensitive to cocaine (Cregler and Mark 1986 Hoffman et al. 1992). However, there are no experimental data to support this hypothesis. 

Nation JR, Liver,ore CL, Burkey RT. 1996. Chronic lead exposure attenuates sensitization to the locomotor-stimulating effects of cocaine. Drug Alcohol Dependence 41 143-149. 

Scheme 42. Two pathways for the N-demethylation of cocaine by mammalian liver microsomal enzyme preparations.

It, thus, appears that the capacity to catalyze reactions of transesterification and esterification is a characteristic of various hydrolases (Chapt. 3). Apart from the carboxylesterases discussed here, lipoprotein lipase has the capacity to synthesize fatty acid ethyl esters from ethanol and triglycerides, or even fatty acids [127]. Ethanol, 2-chloroethanol, and other primary alcohols serve to esterify endogenous fatty acids and a number of xenobiotic acids [128-130]. In this context, it is interesting to note that the same human liver carboxylesterase was able to catalyze the hydrolysis of cocaine to benzoylecgonine, the transesterification of cocaine, and the ethyl esterification of fatty acids [131]. 

S. M. Roberts, R. D. Harbison, R. C. James, Inhibition by Ethanol of the Metabolism of Cocaine to Benzoylecgonine and Ecgonine Methyl Ester in Mouse and Human Liver , Drug Metab. Dispos. 1993, 21, 537-541. 

D. J. Stewart, T. Inaba, M. Lucassen, W. Kalow, Cocaine Metabobsm - Cocaine and Norcocaine Hydrolysis by Liver and Serum Esterases , Clin. Pharmacol. Ther. 1979, 25, 464-468. 

M. R. Brzezinski, B. J. Spink, R. A. Dean, C. E. Berkman, J. R. Cashman, W. F. Bosron, Human Liver Carboxylesterase hCE-1 Binding Specificity for Cocaine, Heroin, and Their Metabobtes and Analogs , Drug Metab. Dispos. 1997, 25, 1089-1096. 

M. R. Brzezinski, T. L. Abraham, C. L. Stone, R. A. Dean, W. F. Bosron, Purification and Characterization of a Human Liver Cocaine Carboxylesterase That Catalyzes the Production of Benzoylecgonine and the Formation of Cocaethylene from Alcohol and Cocaine , Biochem. Pharmacol. 1994, 48, 1747- 1755. 

Once in the blood stream, cocaine levels quickly rise in the brain, faster than plasma levels, which then redistribute to other tissues. Cocaine is rapidly metabolized in the blood and liver, with a half-life of 30 to 90 minutes. The major metabolites have a half-life of approximately 8 hours. Although cocaine itself is detected in urine for only 12 hours, the metabolite benzoylecgonine can be detected in urine for at least 48 hours and sometimes up to 2 weeks. Concurrent use of cocaine and ethanol produces an ethyl ester of benzoylecgonine called cocaethylene. Cocaethylene is an active metabolite, blocking dopamine reuptake, and potentiating the effect of cocaine. Thus, concurrent use of cocaine and ethanol can further increase the additional effects of the drugs and the risk of dependency. 

Other important components of the initial evaluation include a medical evaluation including both a medical history and physical examination. This can identify medical consequences of substance abuse, such as liver impairment from chronic alcohol abuse or sinus complications from cocaine use, as well as reveal needle tracks from a variety of self-injection sites that might not be readily apparent to casual observation. 

Local anesthetics with an amide linkage (and one ester-lined anesthetic, cocaine) are almost completely metabolized by the liver before excretion. However, the total dose administered and the degree of drug accumulation resulting from the initial and subsequent doses are still a concern. 

In humans, the principal route of metabolism of cocaine is by hydrolysis of the ester linkages. Pseudocholinesterase and liver esterases produce the inactive metabolite, ecgonine methyl ester (EME) (Figure 4.5). The second major metabolite, BE, is formed spontaneously at physiological pH. In addition, there is evidence that BE may be formed enzymatically from cocaine by liver carboxylesterases. N-Demethylation of BE produces benzoylnorecgonine. Further metabolism of EME and BE produces ecgonine. Further hydrolysis of cocaine and BE produces minor metabolites, meta- and para-hydroxy-cocaine and -BE. The proportion of each metabolite produced and the activity of the individual metabolites have yet to be completely determined. 

When cocaine is coadministered with ethanol, cocaethylene (CE) is formed in the liver by transesterification by liver methylesterase. CE may also be formed by fatty acid ethyl synthase.16 This lipophilic compound crosses the blood-brain barrier and is known to contribute to the psychological effects produced by cocaine.1 Harris et al.17 administered deuterium-labeled cocaine (0.3 to 1.2 mg/kg) intravenously 1 h after an oral dose of ethanol (1 g/kg) to ten volunteers. When... 

Cocaine is metabolized very quickly by the body. Within minutes, enzymes in the blood and in the liver split the cocaine molecule into two halves, rendering it inactive. Cocaine and its metabolites are excreted in the urine. The body s efficient metabolism of cocaine causes the high to be relatively short-lived. This often causes cocaine users to take several doses of cocaine in a short time, which can increase the chances of an overdose. 

EME and BEG, which is mainly obtained by enzymatic hydrolysis, represents respectively the 32-49 % and 29 45 % of total urinary metabolites cocaine can be converted, in small amounts, to norcocaine (NCOC) and psychoactive metabolite norbenzoylecgonine (NBE). The combined intake of alcohol and cocaine determines the formation of a pharmacologically active metabolite, the cocaethylene (ethyl ester of benzoylecgonine, CE), with a significant liver toxicity [13],... 

Pharmacokinetics Amphetamines are completely absorbed from the gastrointestinal tract, metabolized by the liver, and excreted in the urine. Amphetamine abusers often administer the drugs by intravenous injection and by smoking. The euphoria caused by amphetamine lasts 4 to 6 hours, or 4 to 8 times longer than the effects of cocaine. The amphetamines produce addiction—dependence, tolerance and drug-seeking behavior. 

Hurtova M, Duclos-Vallee JC, Saliba F, Emile JF, Bemelmans M, Castaing D, Samuel D. Liver transplantation for fulminant hepatic failure due to cocaine intoxication in an alcoholic hepatitis C virus-infected patient. Transplantation 2002 73(l) 157-8. 

Cocaine has been associated with liver toxicity (SEDA-14, 32 SEDA-13, 27). 

A 23-year-old man became unresponsive and had a seizure after taking cocaine and alcohol (201). Severe liver necrosis developed and hepatocellular damage was documented with "mTc-PYP imaging. 

Acute hepatitis induced by intranasal cocaine, with transient increases in liver enzymes, has been reported in three HIV-positive patients (202). All had non-active chronic viral hepatitis with normal immunological status one was seropositive for hepatitis B virus and two were positive for hepatitis C virus. A few days after intranasal cocaine use, serum transaminases rose to high values, and two of the patients had fever, stiffness, sweats, and hepatomegaly. Alcohol and hepatotoxic agents were ruled out. Within a few days, the clinical and laboratory signs of hepatitis improved in all three cases. 

The authors suggested that this patient had a defect in lipid metabolism, based on the muscle biopsy. Muscle mitochondria are a principle site for beta-oxidation of fatty acids. Microvesicular steatosis can progress to liver failure with severe and prolonged impairment of beta-oxidation. This metabolic defect may have exacerbated the direct toxic effects of cocaine. 

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