Cocaine liver toxicity

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],... 

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

Concomitant drug use Alcohol, isoniazid, methadone, cocaine or metamphetamine use has been correlated with increased liver toxicity Taiwo (2006) Buyse et al. (2006)... 

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. 

Amphetamines are more toxic than cocaine and, when abused, cause worse problems. The body has a great capacity to metabolize and eliminate cocaine the liver can detoxify a lethal dose of cocaine every thirty minutes. It cannot handle amphetamines as efficiently. At the same time, people can establish stable relationships with amphetamines more easily than they can with cocaine, probably because the intensely pleasureful but very short effect of cocaine is more seductive and invites repetitive dosing. 

A novel metabolite of methylphenidate, ethylphenidate, has recently been detected in human blood and liver samples obtained from two suicide victims who had taken a large dose of methylphenidate and ethanol (49). The concentrations of ethylphenidate were small relative to those of methylphenidate and ritalinic acid. Nevertheless, given the frequent occurrence of methylphenidate and ethanol co-ingestion, the detection of ethylphenidate warrants further studies on the extent of its formation, as well as any associated toxicity associated with normal doses. A transesterification reaction, analogous to that known to produce cocaethylene after cocaine and ethanol co-ingestion (50), has been described with methylphenidate (51). 

Thus truxilline (3) (isatropyl-cocaine) has no anesthetic action, but is a strong cardiac poison, and Ehrlich (4) found that, of several different cocaine derivatives, such as isatropyl-cocaine, valeryl-cocaine hydriodide, and phenylacetyl-cocaine hydriodide, the last named was the only one which had anesthetic properties, but to a less degree than cocaine. All of these have a characteristic toxic effect on the liver, and differ from cocaine only in having the benzoyl group replaced by the one named. 

Cocaine metabolism and disposition following acute ethanol administration were studied in the rat to determine if the in vitro effects of ethanol on cocaine methyl esterase and ethyl transferase activities had significance in vivo (Zachman et al. 1993). The rat was used as it possesses both ethyl transferase and methyl esterase activities, is frequently employed for behavioral and toxicity studies of cocaine, and the size provides sufficient tissue for anal 4 ical work. This study was designed to address three questions. First, do significant concentrations of cocaethylene form and accumulate in tissues with controlled coadministrations of cocaine and alcohol Second, does ethanol administration significantly diminish the hydrolysis of cocaine to benzoylecgonine and methanol, as occurs in vitro when cocaine and ethanol are coincubated with purified human liver carboxylesterase (Brzezinski et al. 1994 Dean et al. 1991) Third, does ethanol inhibition of cocaine methyl ester hydrolysis increase the N-oxidative metabolism of cocaine, as noted when rodents are pretreated with nonspecific esterase inhibitors (Thompson etal. 1979) ... 

Conners and associates (1989) have investigated interactive toxicity of cocaine with phenobarbitol, morphine, and ethanol in organ-cultured human and rat liver slices. 

Hydrolysis of ester linkages has been found to occur in all animals and bacteria however, the relative rates of hydrolysis in various species can be significantly different. In the case of local anesthetics, their metabohc disposition is of great practical importance since their toxicity depends largely on the balance between their rate of absorption and their rate of destruction. In most animals the esterases which hydrolyze many local anesthetics occur both in the liver and in the plasma. In the case ot human plasma, esterase activity is high and is principally responsible for the inactivation of procaine [60]. Cocaine is principally destroyed by liver esterase in the human, whereas plasma esterase in the rabbit is responsible for the hydrolysis of cocaine. The horse has little effective esterase activity against procaine in either plasma or liver and manifests central nervous system stimulation because of the slow destruction of the drug [61]. 

Gao, Y, Geng, L., Orson, R, et al., 2013. Effects of anti-cocaine vaccine and viral gene transfer of cocaine hydrolase in mice on cocaine toxicity including motor strength and liver damage. Chem. Biol. Interact. 203, 208-211. 

Norcocaine 2, the demethylated metabolite of cocaine 1, is detected soon after administration of the parent drug. This transformation be the initial step in a metabolic sequence leading to the observed toxicity. Microsomes in the liver and brain further oxidize 2 to the. nitroxide which may be intimately involved in a variety of free... 

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