Subacute Cocaine Treatment Changes Expression of Mouse Liver Cytochrome P450 Isoforms

Powers, James F.; Shuster, Louis

doi:10.1159/000028271

Cited by 6 publications

(11 citation statements)

References 21 publications

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“…The effect of chronic cocaine administration on its own pharmacokinetics and metabolite pro®le is not clear. In-vitro, microsomal studies suggest that cocaine pretreatment may enhance cocaine metabolite formation (Sandberg et al 1993;Powers & Shuster 1999). However, we did not observe a change in the pharmacokinetics of cocaine or its metabolite formation after prolonged cocaine infusion.…”

Section: Parametercontrasting

confidence: 64%

Chronic Continuous Cocaine Infusion in Rats: Effect on Urine Cocaine, Ecgonine Methylester and Benzoylecgonine Concentrations and Bolus-dose Cocaine Pharmacokinetics

Mets

Soo

Diaz

et al. 2000

Journal of Pharmacy and Pharmacology

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The aim of this study was to determine the effect of chronic cocaine infusion on urine cocaine, ecgonine methylester and benzoylecgonine concentrations to establish if they varied with dose and duration of cocaine administration. Male rats were continuously infused with cocaine at either 6 or 18 mg kg(-1) daily for 13 days. Three urine samples taken over the course of the infusion period showed that cocaine, ecgonine methylester and benzoylecgonine concentrations varied with the dose administered and the duration of administration. Cocaine, ecgonine methylester and benzoylecgonine concentrations were 2-3 times greater in the high-dose group than the low-dose group at each sampling time point. These decreased, respectively, from 7.0+/-1.1, 26.7+/-4.5 and 29.5+/-5.4 microg mL(-1) to 2.5+/-0.5, 10.5+/-1.8 and 11.8+/-1.5 microg mL(-1) in the high-dose group and from 1.0+/-0-2, 7.8+/-1.5 and 6.3+/-0.1 microg mL(-1) to 0.5+/-0.1, 4.0+/-0.6 and 3.1+/-0.4 microg mL(-1) in the low-dose group (P < 0.05) over the infusion period. We also studied the pharmacokinetic and metabolic profile of an intravenous bolus dose of 2.5 mg kg(-1) cocaine hydrochloride after a similar cocaine infusion in rats. Cocaine pharmacokinetics and the profile of ecgonine methylester, benzoylecgonine and norcocaine were no different from rats chronically infused with saline for the same period. Altered cocaine metabolism could not explain the effect of the duration of cocaine infusion on altered metabolite concentrations in urine. Ecgonine methylester/benzoylecgonine urine concentration ratios did not alter with duration of infusion (1.2+/-0.2 and 1.1+/-0.2 in the high-dose group at the first and last time point) and were not affected by the dose of cocaine (1.3+/-0.6 and 1.2+/-0.1 at corresponding times in the low-dose group (P > 0.05)). We conclude that chronic cocaine infusion does not alter cocaine metabolism. This was not reflected by absolute cocaine metabolite urine concentrations, which varied with time, but was represented by urine ecgonine methyl ester/benzoylecgonine concentration ratios.

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Section: Parametercontrasting

confidence: 64%

Chronic Continuous Cocaine Infusion in Rats: Effect on Urine Cocaine, Ecgonine Methylester and Benzoylecgonine Concentrations and Bolus-dose Cocaine Pharmacokinetics

Mets

Soo

Diaz

et al. 2000

Journal of Pharmacy and Pharmacology

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“…They presented evidence that cocaine administered chronically damaged the liver, and discussed the possibility that cocaine itself induced mixed-function oxidase in the smooth endoplasmic reticulum. Later studies have demonstrated that subacute cocaine treatment accounts for increased Nhydroxilation of norcocaine in the mouse liver (21).…”

Section: Resultsmentioning

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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“…27 28 Since chronic application of drugs that are metabolized by cytochrome P450, e.g. cocaine, 29 theophylline and midazolam, 30 can induce metabolism of cytochrome P450, it is possible that a similar phenomenon could be responsible for the decrease in the total and free plasma concentration of ropivacaine during chronic administration. Any other incidents interfering with ropivacaine metabolism can be excluded in our study.…”

Section: Discussionmentioning

confidence: 99%

Ropivacaine plasma concentrations during 120-hour epidural infusion

Wiedemann

Mühlnickel

Staroske

et al. 2000

British Journal of Anaesthesia

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The pharmacokinetics of ropivacaine were evaluated during long-term continuous epidural analgesia (CEDA) for about 120 h. The total and free plasma concentrations of ropivacaine and the alpha1-acid glycoprotein (AAG) concentration were measured in 12 patients after total knee arthroplasty. The infusion rate was adjusted according to patients' analgesic needs or side effects. The mean (SD) rate of infusion of ropivacaine (Naropin 2 mg ml(-1)) was 14.6 (3.2) mg h(-1) on the day of surgery and was increased after surgery to 15.4 (4.4) mg h(-1) on days 1-5. This was equivalent to an absolute dose of 1786 (553) mg of ropivacaine over the entire infusion period. After an initial increase, the mean free ropivacaine plasma concentration nearly plateaued and than decreased slightly after approximately 70 h. The individual peak free plasma concentration was 0.096 (0.034) microg ml(-1). The highest individual free plasma concentration was 0.16 microg ml(-1). The individual peak total plasma concentration, 4.1 (1.2) microg ml(-1), was achieved after 67.7 (16.5) h, although the AAG concentration increased throughout the observation period. Our data support the safety and efficacy of long-term ropivacaine CEDA.

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Subacute Cocaine Treatment Changes Expression of Mouse Liver Cytochrome P450 Isoforms

Cited by 6 publications

References 21 publications

Chronic Continuous Cocaine Infusion in Rats: Effect on Urine Cocaine, Ecgonine Methylester and Benzoylecgonine Concentrations and Bolus-dose Cocaine Pharmacokinetics

Chronic Continuous Cocaine Infusion in Rats: Effect on Urine Cocaine, Ecgonine Methylester and Benzoylecgonine Concentrations and Bolus-dose Cocaine Pharmacokinetics

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

Ropivacaine plasma concentrations during 120-hour epidural infusion

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