Effects of quinidine and cimetidine on the methamphetamine level in the rat brain.

Suzuki, Tsutomu; Chiang, Horng-Jen Fan; Misawa, Miwa

doi:10.1254/jjp.43.103

Jpn.J.Pharmacol

1987

DOI: 10.1254/jjp.43.103

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Effects of quinidine and cimetidine on the methamphetamine level in the rat brain.

Tsutomu Suzuki

Horng-Jen Fan Chiang

Miwa Misawa

Abstract: Abstract-The drug interaction between methamphetamine and quinidine/ cimetidine was investigated in terms of distribution of methamphetamine to the brain. The concentrations of methamphetamine and amphetamine in the brain after an s.c. Injection of methamphetamine were determined in rats pretreated with a single oral dose of quinidine or cimetidine.Both drugs markedly enhanced the increase in the concentrations of methamphetamine and its metabolite, ampheta mine. These results suggest that the recent finding o… Show more

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Cited by 6 publications

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“…[29][30][31] When CMT is combined with MA, levels of both MA and AMP were significantly higher in the rat CNS compared to rats that did not receive CMT. 32 CMT is metabolized by P450 enzymes to its major metabolite, an S-oxide. 27,29,33 The half-life of CMT is relatively short (2-4 hours) and is quickly cleared from the body by urinary excretion (70% of unchanged CMT) or the S-oxide form (20%).…”

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Interactions between Over-the-Counter and Illicit Drugs Utilizing Cytochrome P450 Metabolism: Potential for Exacerbation of Pharmacological Response

Wallace¹,

Crosswy²

2017

Toxicol Forensic Med Open J

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Citation ResearchAbSTRACT Aim: To determine the interaction of over-the-counter (OTC) and illicit psychostimulants at the cytochrome P450 enzyme, CYP2D6. CYP2D6 is responsible for 20% of hepatic Phase I metabolism and is a site of drug-drug interactions, leading to increased drug toxicity. Materials and Methods: We examined the effects the OTC drugs; 1) the prototype H 2 -antagonist cimetidine (CMT) and 2) the opioid agonist cough suppressant dextromethorphan (DEX); as well as two scheduled drugs, methamphetamine (MA) and 3,4-methylenedioxymethamphetamine (MDMA) for their ability to interfere with CYP2D6 activity. Assays with human CYP2D6 determined the inhibitory potential (IC 50 ) of each drug. Kinetic analysis (V max and K m ) was accomplished using rodent hepatic microsomes. Results: Maximum inhibition of CYP2D6 activity following exposure to CMT+MDMA was significantly reduced 75-85% compared to quinidine (control) values. These data showed inhibitory effects in CYP2D6 activity in each compound tested. Alterations in CYP2D6 activity may result in complex drug-drug interactions leading to elevated plasma levels of drugs and increased risk for toxicity. Assays using rat CYP2D2 demonstrated V max elevations in the CMT group (493%) compared to control (naïve, no treatment) values (19.9±5.1 pmol/mg protein/ min). The K m was increased 218% in CMT compared to controls (3.1±0.5 μM). Collectively, all MA challenged groups exhibited increases in total enzyme [V max ; 280-490%] and affinity [K m ; 165-220%] values compared to the control group. The increase in both V max and K m suggests that the low affinity/high capacity CYP2D2 isoform is upregulated. Conclusion: Our findings suggest that in vivo, MA acts as a CYP2D2-inducer, which will lead to altered secondary drug metabolism, increasing the risk of drug-related toxicity. Coupled with the ability of CMT and DEX to interfere with MA metabolism, a complex drug-drug interaction is possible, leading to increased toxicity. Our findings substantiate the hypothesis that the combination of illicit and OTC drugs could result in complex drug-drug interactions increasing the risk for severe drug-related toxicity.

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confidence: 99%

Interactions between Over-the-Counter and Illicit Drugs Utilizing Cytochrome P450 Metabolism: Potential for Exacerbation of Pharmacological Response

Wallace¹,

Crosswy²

2017

Toxicol Forensic Med Open J

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Effects of high-dose methamphetamine administration on serotonin uptake sites in rat brain measured using [3H]cyanoimipramine autoradiography

Kovachich¹,

Aronson²,

Brunswick³

1989

Brain Research

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The effect of repeated administration of methamphetamine on dopamine uptake sites in rat striatum

Ikawa

Watanabe

Motohashi³

et al. 1994

Neuroscience Letters

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Effects of quinidine and cimetidine on the methamphetamine level in the rat brain.

Cited by 6 publications

References 15 publications

Interactions between Over-the-Counter and Illicit Drugs Utilizing Cytochrome P450 Metabolism: Potential for Exacerbation of Pharmacological Response

Interactions between Over-the-Counter and Illicit Drugs Utilizing Cytochrome P450 Metabolism: Potential for Exacerbation of Pharmacological Response

Effects of high-dose methamphetamine administration on serotonin uptake sites in rat brain measured using [3H]cyanoimipramine autoradiography

The effect of repeated administration of methamphetamine on dopamine uptake sites in rat striatum

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