Metabolism of Dextromethorphanin vitro: Involvement of Cytochromes P450 2D6 AND 3A3/4, with a Possible Role of 2E1

Schmider, Jürgen; Greenblatt, David J.; Fogelman, Steven M.; Moltke, Lisa L. von; Shader, Richard I.

doi:10.1002/(sici)1099-081x(199704)18:3<227::aid-bdd18>3.0.co;2-l

Cited by 76 publications

(47 citation statements)

References 19 publications

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“…This agrees with experiment, in that the corresponding metabolite is not observed (27). In order to explain the large difference between the QM and QM/MM activation energies, we studied in detail the QM and QM/MM TS structures.…”

Section: Simulations and Qm/mm Calculationsmentioning

confidence: 99%

“…Dextromethorphan has frequently been used as a probe drug in clinical studies of metabolism, and there is abundant data available on its metabolites. It is O-demethylated by P450 2D6 (27), although N-demethylation can also occur at high substrate concentration or with other isoforms, and with mutation of active site residues other products have also been observed (28) Aromatic oxidation of dextromethorphan in P450s is never observed, although this is a major metabolic route for other methoxyaromatic rings (e.g., anisole) (29-31) (Scheme 1).…”

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confidence: 99%

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Understanding the determinants of selectivity in drug metabolism through modeling of dextromethorphan oxidation by cytochrome P450

Oláh

Mulholland

Harvey

2011

Proc. Natl. Acad. Sci. U.S.A.

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Cytochrome P450 enzymes play key roles in the metabolism of the majority of drugs. Improved models for prediction of likely metabolites will contribute to drug development. In this work, two possible metabolic routes (aromatic carbon oxidation and O-demethylation) of dextromethorphan are compared using molecular dynamics (MD) simulations and density functional theory (DFT). The DFT results on a small active site model suggest that both reactions might occur competitively. Docking and MD studies of dextromethorphan in the active site of P450 2D6 show that the dextromethorphan is located close to heme oxygen in a geometry apparently consistent with competitive metabolism. In contrast, calculations of the reaction path in a large protein model [using a hybrid quantum mechanical-molecular mechanics (QM/MM) method] show a very strong preference for O-demethylation, in accordance with experimental results. The aromatic carbon oxidation reaction is predicted to have a high activation energy, due to the active site preventing formation of a favorable transition-state structure. Hence, the QM/MM calculations demonstrate a crucial role of many active site residues in determining reactivity of dextromethorphan in P450 2D6. Beyond substrate binding orientation and reactivity of Compound I, successful metabolite predictions must take into account the detailed mechanism of oxidation in the protein. These results demonstrate the potential of QM/MM methods to investigate specificity in drug metabolism.C ytochrome P450 enzymes (P450s) form one of the most powerful defense mechanisms of living organisms: They protect against xenobiotics via an oxidative pathway, which in most instances leads to a less harmful and more soluble product with faster excretion. The same mechanism is involved in the metabolism of most drugs and alters the pharmacological activity of many drugs. As a consequence, P450-mediated transformations of drug candidates are of crucial importance in the pharmaceutical industry. The roles of P450s are manifold. Oxidation by P450s can lead to toxic products, but, on the other hand, local activation of, e.g., anticancer prodrugs by P450s to lethal intracellular toxins at the site of the tumor is an important strategy (1). Drug compounds can induce P450 expression but can also inhibit them in various ways (2-4). The metabolic clearance of most drugs depends on P450s, and they have been implicated in a large number of drug-drug interactions (5, 6), which can result in fatalities (7,8). Interactions of drug candidates with P450s must be taken into account during the drug discovery process if the expensive and time-consuming development of active compounds with hidden toxic effects is to be avoided.It is increasingly recognized that methods capable of predicting P450 oxidative activity for a given substrate, and also the predominant site(s) of metabolism, could contribute significantly to drug development. There are many aspects to this problem, including isoform selectivity (i.e., which P450 isoform will contribute mos...

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Section: Simulations and Qm/mm Calculationsmentioning

confidence: 99%

mentioning

confidence: 99%

Understanding the determinants of selectivity in drug metabolism through modeling of dextromethorphan oxidation by cytochrome P450

Oláh

Mulholland

Harvey

2011

Proc. Natl. Acad. Sci. U.S.A.

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“…60 It is clear that OTC drugs such as CMT and DEX can play a significant role in the development of drug-drug interactions leading to increased toxicity by interference with CYP2D6 metabolism. There is an extensive body of work regarding the metabolism of MA and MDMA.…”

Section: Inhibition Studies Purified Cyp2d6mentioning

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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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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“…Instead of acting as a direct antagonist of the NMDA receptor itself, dextromethorphan likely functions as a pro-drug to its nearly 10-fold more potent metabolite dextromethorphan, and this is the true mediator of its dissociative effects (Chou et al, 1999). (+)-3-methoxymorphinan, dextromethorphan's other major metabolite, plays role in its effects, but it is not entirely clear (Schmider et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

Study of Interaction of Dextromethorphan Hydrobromide with Deoxyribonucleic Acid by Fluorescence Quenching

et al. 2016

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Interactions with many clinically active therapeutic agents with deoxyribonucleic acid (DNA) are well studied and it expedites deciphering the structure of DNA and to investigate the pathological implication of those molecules in a living organism. The interaction of dextromethorphan hydrobromide (DEX) with calf thymus DNA (ct DNA) was studied employing UV absorption and fluorescence spectroscopic techniques. The binding affinity of DEX to DNA was calculated at different temperatures and the stoichiometry of binding was characterized to be about 1 dextromethorphan molecule per nucleotide. Hypochromic effect was found in the absorption spectra of dextromethorphan, and its wavelength had no shift in the presence of DNA indicating external binding mode of dextromethorphan to DNA. Quenching constants 3532 L/ mol and 12446L/ mol at 298 K and 308 K respectively with correlation co-efficient of 0.974 and 0.976, using SternVolmer equation and the quenching mechanism was found to be dynamic. Fluorescence spectroscopic results showed the quenching of fluorescence intensity of DEX in the presence of DNA, indicating the interaction between DEX and DNA. Based on this, hydrophobic interaction were found to play the dominating role in DEX-DNA binding and those binding forces also indicate the binding site of dextromethorphan to be in the minor groove of DNA.

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Metabolism of Dextromethorphanin vitro: Involvement of Cytochromes P450 2D6 AND 3A3/4, with a Possible Role of 2E1

Cited by 76 publications

References 19 publications

Understanding the determinants of selectivity in drug metabolism through modeling of dextromethorphan oxidation by cytochrome P450

Understanding the determinants of selectivity in drug metabolism through modeling of dextromethorphan oxidation by cytochrome P450

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

Study of Interaction of Dextromethorphan Hydrobromide with Deoxyribonucleic Acid by Fluorescence Quenching

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