Mexiletine effects on theophylline disposition

Hurwitz, Aryeh; Vacek, James L.; Botteron, G.W.; Sztern, M; Hughes, Edward M.; Jayaraj, A. P.

doi:10.1038/clpt.1991.140

Cited by 25 publications

(13 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, the involvement of CYP1A2 in mexiletine hydroxylase activity is suggested by some observations. Firstly, mexiletine reduces theophylline clearance by inhibiting N ‐demethylation of theophylline which is catalyzed by CYP1A2 [14]. Secondly, cigarette smoking induces 2‐hydroxylation of mexiletine [26].…”

Section: Discussionmentioning

confidence: 99%

“…It has been reported that the formation of these metabolites is catalyzed by CYP1A2 in humans [12, 13]. Mexiletine was reported to reduce theophylline clearance and subsequently increase its plasma concentration by inhibiting N ‐demethylation of theophylline [14]. Therefore, the involvement of CYP1A2 in mexiletine metabolism is suggested.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Involvement of CYP1A2 in mexiletine metabolism

Nakajima

Kobayashi

Shimada³

et al. 1998

Brit J Clinical Pharma

View full text Add to dashboard Cite

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...

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Involvement of CYP1A2 in mexiletine metabolism

Nakajima

Kobayashi

Shimada³

et al. 1998

Brit J Clinical Pharma

View full text Add to dashboard Cite

show abstract

“…The respective K m value in the presence of mexiletine (Table 3) or propafenone (Table 4) Table 2). phylline, which had been widely documented [19][20][21][22][23][24], Inhibition of mexiletine and propafenone on phenacetin appears to be by inhibition of CYP1A2. Thus, it seems O-deethylation in recombinant CYP1A2…”

Section: Kinetic Analysis Of Phenacetin O-deethylation In Human Livermentioning

confidence: 99%

“…In addition, propafenone and mexiletine inhibited phenacetin O-deethylation catalysed by cDNA-expressed CYP1A2. Conclusions These data suggest that, among the antiarrhythmic drugs studied, propafenone and mexiletine are relatively potent inhibitors of CYP1A2, which may cause a drug-drug interaction with drugs metabolized by CYP1A2.Keywords: CYP1A2, phenacetin O-deethylation, human liver microsomes, mexiletine, propafenone I antiarrhythmic drug, has been reported to elevate plasma Introduction levels of concomitantly administered theophylline [19][20][21][22][23][24], by inhibiting 1-and 3-demethylation and 8-hydroxylation Cytochrome P450 1A2 (CYP1A2), an isoform of the CYP1A subfamily [1], accounts for about 10 to 15% of the total CYP of theophylline [19,20]. Recent studies using human liver microsomes and cDNA-expressed human CYP isoforms content of human livers [2].…”

mentioning

confidence: 99%

Inhibitory effects of antiarrhythmic drugs on phenacetin O-deethylation catalysed by human CYP1A2

Kobayashi¹,

Nakajima²,

Chiba³

et al. 1998

Br J Clin Pharmacol

View full text Add to dashboard Cite

AimsThe aim of the study was to clarify whether the pharmacokinetic interaction between theophylline and mexiletine is mediated by inhibition of CYP1A2 and to assess the possible interaction potential of other antiarrhythmic drugs with drugs metabolized by CYP1A2. Methods The inhibitory effects of mexiletine and 10 antiarrhythmic drugs on phenacetin O-deethylation, a marker reaction of CYP1A2, were studied using human liver microsomes and cDNA-expressed CYP1A2. Results Propafenone and mexiletine inhibited phenacetin O-deethylation with IC 50 values of 29 and 37 mm, respectively. Disopyramide, procainamide and pilsicainide produced negligible inhibition of phenacetin O-deethylation (IC 50 >1 mm). Amiodarone, bepridil, aprindine, lignocaine, flecainide and quinidine inhibited phenacetin O-deethylation in a concentration-dependent manner, although the inhibitory effects were relatively weak with IC 50 values ranging from 86 to 704 mm. Propafenone and mexiletine selectively abolished the high-affinity component of phenacetin O-deethylation in human liver microsomes. In addition, propafenone and mexiletine inhibited phenacetin O-deethylation catalysed by cDNA-expressed CYP1A2. Conclusions These data suggest that, among the antiarrhythmic drugs studied, propafenone and mexiletine are relatively potent inhibitors of CYP1A2, which may cause a drug-drug interaction with drugs metabolized by CYP1A2.Keywords: CYP1A2, phenacetin O-deethylation, human liver microsomes, mexiletine, propafenone I antiarrhythmic drug, has been reported to elevate plasma Introduction levels of concomitantly administered theophylline [19][20][21][22][23][24], by inhibiting 1-and 3-demethylation and 8-hydroxylation Cytochrome P450 1A2 (CYP1A2), an isoform of the CYP1A subfamily [1], accounts for about 10 to 15% of the total CYP of theophylline [19,20]. Recent studies using human liver microsomes and cDNA-expressed human CYP isoforms content of human livers [2]. This enzyme is known to catalyse the metabolism of imipramine [3], propranolol [4], indicated that CYP1A2 is the enzyme mainly responsible for the 1-and 3-demethylation and 8-hydroxylation of clozapine [5], caffeine [6], theophylline [7] and phenacetin [6,8]. The kinetic disposition of these drugs is altered by the theophylline in humans [25, 26]. Several studies using rat liver microsomes also showed that mexiletine inhibits administration or exposure to inducers or inhibitors of CYP1A2. For example, the clearance of propranolol [9], ethoxyresorufin O-dealkylation catalysed by CYP1A1, another isoform of the CYP1A subfamily [27]. However, in clozapine [10] and theophylline [11] is greater in smokers than in nonsmokers, as a result of marked induction of vivo [28,29] and in vitro [30,31] studies showed that mexiletine is mainly metabolized by CYP2D6. Therefore, CYP1A2 by cigarette smoking. On the other hand, the plasma concentrations of imipramine [12], clozapine [13], it remains obscure as to whether the pharmacokinetic interaction between theophylline and mexiletine occurs by caffeine [14,...

show abstract

“…It is well recognized that the metabolism of theophylline can be perturbed by coadministration of other agents that modify the activities of selected cytochrome P450 (CYP) isoenzymes (Upton, 1991). Recent studies have shown that the antiarrhythmic agent mexiletine lowers the plasma clearance of theophylline by 40-45% and increases its half-life by a factor of 2 (Hurwitz et al, 1991;Loi et al, 1991;Stoysich et al, 1991). A preferential inhibition of the demethylation of theophylline metabolism has also been shown (Hurwitz et al, 1991;Loi et al, 1991).…”

Section: Introductionmentioning

confidence: 99%

The effect of tocainide on theophylline metabolism.

Loi

Wei

Parker

et al. 1993

Brit J Clinical Pharma

View full text Add to dashboard Cite

The effect of 5 days of oral tocainide (400 mg every 8 h) on the kinetics of theophylline given as a single 5 mg kg-1 i.v. infusion over 30 min was investigated in eight healthy male nonsmokers. Treatment with tocainide decreased the plasma clearance of theophylline from 37.5 ± 6.9 (mean ± s.d.) to 33.7 ± 5.0 ml kg-' h-1 (difference -3.8, 95% CI, -1.7 to -5.9; P = 0.004) and increased its terminal elimination half-life from 9.7 ± 2.5 to 10.4 ± 2.1 h (difference 0.7, 95% CI, 0.2 to 1.2; P = 0.011). Tocainide decreased the formation clearances of 3-methylxanthine and 1-methyluric acid, but the formation clearance of 1 ,3-dimethyluric acid was unaltered. These data indicate that tocainide exerts a modest inhibitory effect on theophylline metabolism. The magnitude of this change is substantially smaller than that reported to be produced by mexiletine.

show abstract

Mexiletine effects on theophylline disposition

Cited by 25 publications

References 0 publications

Involvement of CYP1A2 in mexiletine metabolism

Involvement of CYP1A2 in mexiletine metabolism

Inhibitory effects of antiarrhythmic drugs on phenacetin O-deethylation catalysed by human CYP1A2

The effect of tocainide on theophylline metabolism.

Contact Info

Product

Resources

About