Catalyzation of cocaine <i>N</i>‐demethylation by cytochromes P4502B, P4503A, and P4502D in fish liver

Arınç, Emel; Bozcaarmutlu, Azra

doi:10.1002/jbt.10075

Cited by 19 publications

(11 citation statements)

References 44 publications

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“…Nifedipine is a substrate of CYP 3A and other isoenzymes such as CYP 2B (30,31) which mediate cocaine's N-demethylation to N-hydroxynorcocaine in liver microsomes (32)(33)(34). Our results seem to confi rm this interaction, since nifedipine successfully counteracted cocaine effects when administered in combination.…”

Section: Discussionsupporting

confidence: 56%

Nifedipine Lowers Cocaine-Induced Brain and Liver Enzyme Activity and Cocaine Urinary Excretion in Rats

Vitcheva

Simeonova

Karova³

et al. 2011

Archives of Industrial Hygiene and Toxicology

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The aim of this study was to see how nifedipine counters the effects of cocaine on hepatic and brain enzymatic activity in rats and whether it affects urinary excretion of cocaine. Male Wistar rats were divided in four groups of six: control, nifedipine group (5 mg kg -1 i.p. a day for fi ve days); cocaine group (15 mg kg -1 i.p. a day for fi ve days), and the nifedipine+cocaine group. Twenty-four hours after the last administration, we measured neuronal nitric oxide synthase (nNOS) activity in the brain and cytochrome P450 quantity, ethylmorphine-N-demethylase, and anilinehydroxylase activity in the liver. Urine samples were collected 24 h after the last cocaine and cocaine+nifedipine administration. Urinary cocaine concentration was determined using the GC/MS method. Cocaine administration increased brain nNOS activity by 55 % (p<0.05) in respect to control, which indicates the development of tolerance and dependence. In the combination group, nifedipine decreased the nNOS activity in respect to the cocaine-only group. In the liver, cocaine signifi cantly decreased and nifedipine signifi cantly increased cytochrome P450, ethylmorphine-N-demethylase, and anilinehydroxylase in respect to control. In combination, nifedipine successfully countered cocaine effects on these enzymes. Urine cocaine excretion in the cocaine+nifedipine group signifi cantly dropped (by 35 %) compared to the cocaine-only group. Our results have confi rmed the effects of nifedipine against cocaine tolerance and development of dependence, most likely due to metabolic interactions between them. Vitcheva V, et al. INFLUENCE OF NIFEDIPINE ON COCAINE TOXICITY Arh Hig Rada Toksikol 2011;62:131-137 Multiple cocaine administration leads to behavioural activation, tolerance, and development of dependence in animals and humans (2). These adaptive changes in the central nervous system (CNS) are largely mediated by L-type calcium channels (3). One of the mechanisms underlying drug tolerance and dependence, and the related withdrawal syndrome, is a change in calcium homeostasis and the consequent activation of N-methyl-D-aspartate/nitric oxide (NMDA/NO) cascade (4). Changes in Ca 2+ homeostasis seem to be induced by calcium channel blockers of the 1,4-dihydropyridine type. KEY WORDS: anilinehydroxylase, cytochrome P450, ethylmorphine-N-demethylase, GSH, nNOSIn our earlier studies (5-6), we have demonstrated that nifedipine, co-administered with morphine, attenuates withdrawal symptoms, which correlate with changes in the activity of neuronal nitric oxide synthase (nNOS) (5). Interactions between morphine and nifedipine in the liver and on the level of urine excretion were also observed, probably due to a metabolic interaction between these compounds (6).

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Section: Discussionsupporting

confidence: 56%

Nifedipine Lowers Cocaine-Induced Brain and Liver Enzyme Activity and Cocaine Urinary Excretion in Rats

Vitcheva

Simeonova

Karova³

et al. 2011

Archives of Industrial Hygiene and Toxicology

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“…Isoenzymes involved in cocaine N-demethylation show species differences. In humans and mice cocaine is N-demethylated by CYP 3A, and in rats by both CYP 3A and CYP 2B (3). The involvement of CYP 3A4 in cocaine metabolism implies possible metabolic interactions with other substrates of this isoenzyme, including Ca 2+ channel blockers nifedipine, nimodipine, and amlodipine (4).…”

mentioning

confidence: 99%

Changes In Liver and Brain Cytochrome P450 after Multiple Cocaine Administration, Alone and in Combination with Nifedipine

Vitcheva

Mitcheva

2007

Archives of Industrial Hygiene and Toxicology

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The objective of this study was to evaluate possible changes caused by multiple cocaine administration, alone and in combination with 1,4-dihydropiridine calcium channel blocker nifedipine, on cytochrome P450 levels both in the brain and liver. The experiment was done on male Wistar rats divided in four groups: control, treated with nifedipine (5 mg kg -1 i.p. for five days), treated with cocaine (15 mg kg -1 i.p. for five days), and treated with nifedipine and 30 minutes later with cocaine (also for five days). Total cytochrome P450 was measured spectrometrically in liver and brain microsomes. Multiple administration of cocaine alone and in combination with nifedipine did not change the brain P450 significantly. In the liver, nifedipine significantly increased P450 by 28 % vs. control. In contrast, cocaine significantly decreased P450 by 17 % vs. control. In animals treated with nifedipine and cocaine, cytochrome P450 increased 11 % (p<0.01) vs. control, decreased 12.5 % (p<0.001) vs. nifedipine group and increased 34 % (p<0.0001) vs. cocaine group. These results suggest that the cocaine and nifedipine interact at the metabolic level. Cocaine is an alkaloid psychostimulant with high addictive potential. It has a high affinity for the transporters of dopamine, serotonine and noradrenaline, and blocks their reuptake (1). KEY WORDS: calcium channel blocker, metabolism, microsomes, in vivo interactionsCocaine is extensively metabolized in humans and animals by hepatic and plasma esterases to pharmacologically inactive benzoylecgonine, ecgonine methyl ester (2), and an active metabolite, norcocaine, the product of N-demethylation. Isoenzymes involved in cocaine N-demethylation show species differences. In humans and mice cocaine is N-demethylated by CYP 3A, and in rats by both CYP 3A and CYP 2B (3). The involvement of CYP 3A4 in cocaine metabolism implies possible metabolic interactions with other substrates of this isoenzyme, including Ca 2+ channel blockers nifedipine, nimodipine, and amlodipine (4).Literature data suggest that L-type calcium channels play a principal role in the regulation of adaptive changes in the central nervous system (5). Blockers of these channels are interesting for their potential application as anti-addiction agents, as they appear to play a principal role in the regulation of adaptive changes in the central nervous system by maintaining different types of drug dependence and withdrawal, including those induced by psyhostimulants (6). In our earlier studies (7) we have demonstrated that nifedipine, co-administered with morphine, attenuates the symptoms of opiate withdrawal that correlated with the changes in neuronal nitric oxide synthase (nNOS). At the same time we observed interactions between morphine and nifedipine in the liver.

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“…These include, for instance, ketoconazole (a CYP3A4 inhibitor) which increases exposure to imatinib 5 , or an increase of mean Cmax of simvastatin 6 , a substrate of CYP3A. Our two cases may suggest a likely interference in the cocaine metabolism by imatinib co-administration leading to severe side effects 8 . Conversely, no clear explanation can be given for the concomitant reduction of imatinib efficacy, for which other factors could be hypothesized to independently interfere with drug compliance or cellular pharmacodynamics.…”

mentioning

confidence: 96%

“…Many pharmacological interactions have been described and for a number of drugs plasma levels may be increased by imatinib [5][6][7] . Cocaine is hepatotoxic in several species, including man, and results in the inhibition of CYP2A activities 8 . In fact it is well known in animal models that repeated administration of cocaine decreases CYP1A1/2, CYP2A4/5, CYP2Cx, CYP2E1, CYP3A enzymes activities, which are principally responsible for the Ndemethylation in human and mouse liver microsomes 8 .…”

mentioning

confidence: 99%

“…Cocaine is hepatotoxic in several species, including man, and results in the inhibition of CYP2A activities 8 . In fact it is well known in animal models that repeated administration of cocaine decreases CYP1A1/2, CYP2A4/5, CYP2Cx, CYP2E1, CYP3A enzymes activities, which are principally responsible for the Ndemethylation in human and mouse liver microsomes 8 . Due to the fact that CYP3A4 enzyme is the main responsible for the imatinib metabolism, several cases of drug-drug interactions are reported.…”

mentioning

confidence: 99%

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Cocaine abuse may influence the response to imatinib in CML patients

Breccia¹,

Gentilini²

2007

Haematologica

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Catalyzation of cocaine N‐demethylation by cytochromes P4502B, P4503A, and P4502D in fish liver

Cited by 19 publications

References 44 publications

Nifedipine Lowers Cocaine-Induced Brain and Liver Enzyme Activity and Cocaine Urinary Excretion in Rats

Nifedipine Lowers Cocaine-Induced Brain and Liver Enzyme Activity and Cocaine Urinary Excretion in Rats

Changes In Liver and Brain Cytochrome P450 after Multiple Cocaine Administration, Alone and in Combination with Nifedipine

Cocaine abuse may influence the response to imatinib in CML patients

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