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

Abstract

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.

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

“…Nifedipine given alone showed the opposite effects to cocaine, signifi cantly increasing cytochrome P450 quantity (28 %) and ethylmorphine-N-demethylase (34 %) and anilinehydroxylase (27 %) activity in respect to control. These results are in good correlation with our earlier fi ndings (5,12).…”

“…In our earlier studies, we investigated the effect of cocaine on brain and liver cytochrome P450 after multiple administration in rats and found that the cumulative intraperitoneal (i.p.) dose of 15 mg kg -1 led to a signifi cant increase in the quantity of cytochrome P450 (12) and in ethylmorphine-N-demethylase (CYP 3A) (13) and anilinehydroxylase (CYP 2E1) activity (14). These fi ndings suggest that cocaine and nifedipine interact in the brain and liver.…”

“…This combination was also administered once daily for fi ve days. The selection of nifedipine and cocaine doses was based on our earlier study (12) and on doses commonly used by other laboratories (18,19). Our earlier study (12) demonstrated that 5 mg kg -1 of nifedipine, administered intraperitoneally to male Wistar rats once daily for fi ve days, led to increases in cytochrome P450.…”

“…The selection of nifedipine and cocaine doses was based on our earlier study (12) and on doses commonly used by other laboratories (18,19). Our earlier study (12) demonstrated that 5 mg kg -1 of nifedipine, administered intraperitoneally to male Wistar rats once daily for fi ve days, led to increases in cytochrome P450. The fourth group consisted of control animals, which were treated with saline, involved in the experiment from the very beginning, and housed under the same standard laboratory conditions as the treated animals.…”

Testosterone differentially alters cocaine-induced ambulatory and rearing behavioral responses in adult and adolescent rats

“…Indeed, Vitcheva and Mitcheva (2007) found that cocaine treatment significantly decreased P450 in the liver by 17% as compared with controls, suggesting that cocaine may affect serum testosterone levels. Although it is not clear how cocaine affects liver function in adolescent rats, differences in serum testosterone levels between saline- and cocaine-treated adolescent rats may in part be due to cocaine’s effects on liver enzymes.…”