Ethoxyresorufin O‐deethylation by human liver microsomes.

Williams, FM; Mutch, Elaine; Woodhouse, K. W.; Lambert, Denis; Rawlins,

doi:10.1111/j.1365-2125.1986.tb02885.x

Cited by 15 publications

(8 citation statements)

References 9 publications

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“…The effects of CYP inhibitors on mexiletine p ‐ and 2‐hydroxylase activities in human liver microsomes at a substrate concentration of 20 μm were investigated. The inhibitors studied were furafylline [18], ethoxyresorufin [19], quinidine [20], and bufuralol [21]. The range of concentrations used were 0.25–10 μm for furafylline, ethoxyresorufin and quinidine, 1–100 μm for bufuralol.…”

Section: Methodsmentioning

confidence: 99%

Involvement of CYP1A2 in mexiletine metabolism

Nakajima

Kobayashi

Shimada³

et al. 1998

Brit J Clinical Pharma

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Aims Mexiletine has been reported to be hydroxylated by cytochrome P450 2D6 (CYP2D6) in humans. However, the involvement of CYP1A2 in the metabolism of mexiletine has been proposed based on the interaction with theophylline which is mainly metabolized by CYP1A2. The aim of this study was to clarify the role of human CYP1A2 in mexiletine metabolism. Methods Human CYP isoforms involved in mexiletine metabolism were investigated using microsomes from human liver and B-lymphoblastoid cells expressing human CYPs. The contributions of CYP1A2 and CYP2D6 to mexiletine metabolism were estimated by the relative activity factor (RAF). Results Mexiletine p-and 2-hydroxylase activities in human liver microsomes were inhibited by ethoxyresorufin and furafylline as well as quinidine. Mexiletine p-and 2-hydroxylase activities in microsomes from nine human livers correlated significantly with bufuralol 1∞-hydroxylase activity (r=0.907, P<0.001 and r=0.886, P<0.01, respectively). Microsomes of B-lymphoblastoid cells expressing human CYP1A2 exhibited lower mexiletine p-and 2-hydroxylase activities than those expressing human CYP2D6. It was estimated by RAF that the major isoform involved in mexiletine metabolism was CYP2D6, and the contribution of CYP1A2 to both mexiletine p-and 2-hydroxylase activities was 7-30% in human liver microsomes. However, the K m values of the expressed CYP1A2 (~15 mm) were almost identical with those of the expressed CYP2D6 (~22 mm) and human liver microsomes. Conclusions Mexiletine is a substrate of CYP1A2. The data obtained in this study suggest that the interaction of mexiletine with theophylline might be due to competitive inhibition of CYP1A2.Keywords: cytochrome P450, CYP2D6, bufuralol, ethoxyresorufin, furafylline, cDNAexpressed microsomes, relative activity factor These metabolites have no significant antiarrhythmic activity Introduction [5]. Several in vitro [6,7] and in vivo studies [8,9] have suggested that p-and 2-hydroxymexiletine formation are Mexiletine is a class 1B antiarrhythmic agent used for the control of ventricular arrhythmias. It is of particular value mediated by CYP2D6 in humans. Mexiletine is occasionally used together with theophylline because of its long time course of action and its suitability for either parenteral or oral administration [1]. Numerous in patients who have both cardiac and pulmonary diseases. Recent reports have suggested that mexiletine increases the studies have shown that there is marked interindividual variability in mexiletine plasma concentrations after a given theophylline plasma concentration resulting in theophylline dose. As the antiarrhythmic activity and toxicity of mexiletine is strongly correlated with its plasma concentration and as the therapeutic index is narrow [2], monitoring of the plasma concentration is desirable to ensure efficacy and to reduce the side effects of the drug. Mexiletine is eliminated by both renal excretion of the unchanged compound and extensive hepatic metabolism [1, 3]. Less than 10% of mexiletine is recovered unchan...

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Section: Methodsmentioning

confidence: 99%

Involvement of CYP1A2 in mexiletine metabolism

Nakajima

Kobayashi

Shimada³

et al. 1998

Brit J Clinical Pharma

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“…EROD was assayed fluorometrically according to the methods of Williams et al (19) and Shinjari et al (20) with slight modifications. Two hundred micrograms of HLM, 40 mM ethoxyresorufin, 2 mM NADPH, 100 mM MgCl 2 , and antituberculosis drugs in 200 mM potassium phosphate buffer, pH 7.4 were incubated at 37°C for 15 min (final volume of 500 ml).…”

Section: Direct Inhibitory Effects Of Antituberculosis Drugs On Cyp Amentioning

confidence: 99%

Inhibitory Effect of Antituberculosis Drugs on Human Cytochrome P450-Mediated Activities

et al. 2004

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Abstract. The potential for drug-drug interactions mediated by the inhibition of cytochrome P-450 (CYP) were concerned during antituberculosis therapy. However, the information regarding human CYP inhibition by antituberculosis drugs is limited to isoniazid. In the current study, we examined the inhibitory effects of pyrazinamide and ethionamide, both of which are chemically related to isoniazid, on the CYP-mediated activities in human liver microsomes and compared them to that of isoniazid. No remarkable effects on any CYP activities were observed by pyrazinamide and ethionamide. In contrast, in addition to the reported inhibitory effect of isoniazid on CYP1A2, CYP2A6, CYP2C19, and CYP3A activities, our results newly showed its effect on CYP2C9 and CYP2E1 activities. Isoniazid showed potent direct inhibitory effect on S-warfarin 7-hydroxylation, while a preincubation step in the presence of NADPH was needed to inhibit chlorzoxazone 6-hydroxylation. Furthermore, irreversible inhibition of CYP2C19 activity by isoniazid was also observed in the dilution study. These results suggested that pyrazinamide and ethionamide did not seem to cause drug interactions mediated by the inhibition of CYP. In contrast, isoniazid might contribute to the severe drug interactions by a different inhibitory mechanism depending on each of the CYP isozymes, in addition to the reported observations.

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“…This substrate has been shown in animals (Burke and Mayer 1983) and man (Thompson et al 1984;Williams et al 1986) to be a probe substrate for cytochrome P-450 forms which are involved in the metabolism of polycyclic hydrocarbons.…”

Section: Discussionmentioning

confidence: 95%

“…Ethoxyresorufin 0-deethylase (EROD) has been shown to be a useful probe for cytochrome P450 forms inducible by 3-methylcholanthrene in rat liver (Burke and Mayer 1983). This is probably also true in human liver, where EROD activity is influenced by cigarette smoking (Thompson et al 1984;Williams et al 1986). EROD may therefore be a 'marker' for cytochrome P450 forms which metabolise environmental carcinogens.…”

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confidence: 92%