Mexiletine concentration

CYP450 system Because mexiletine is a substrate for CYP2D6 and CYP1A2, inhibition or induction of either of these enzymes would be expected to alter mexiletine concentrations. 

Mexiletine is mainly cleared polymorphically by CYP2D6 in the liver, and poor metabolizers and the slower among the extensive metabolizers have a higher incidence of mild adverse effects (nausea and light-headedness) (43). However, renal insufficiency can also be associated with an increase in plasma mexiletine concentrations (44). 

Lactation Mexiletine appears in breast milk in concentrations similar to those in plasma. If mexiletine is essential, consider alternative infant feeding. 

An upward adjustment in dose may be required when mexiletine is administered with phenytoin or rifampin, since these drugs stimulate the hepatic metabolism of mexiletine, reducing its plasma concentration. 

MEXILETINE ANTICANCER AND IMMUNOMODULATING DRUGS-IMATINIB Imatinib may cause an T in plasma concentrations of mexiletine and a risk of toxic effects, e.g. nausea, vomiting, constipation, taste disturbances, dizziness and confusion Imatinib is a potent inhibitor of CYP2D6 isoenzymes, which metabolize mexiletine Mexiletine is used for life-threatening ventricular arrhythmias. Close monitoring of BP and ECG is mandatory, and watch for signs and symptoms of heart failure... 

MEXILETINE CNS STIMULANTS-MODAFINIL May cause l mexiletine levels if CYP1A2 is the predominant metabolic pathway and alternative metabolic pathways are either genetically deficient or affected Modafinil is a moderate inducer of CYP1A2 in a concentration-dependent manner Be aware... 

MEXILETINE H2 RECEPTOR BLOCKERS Cimetidine may t plasma concentrations of mexiletine Cimetidine inhibits CYP2D6-mediated metabolism of mexiletine. Ranitidine is a much weaker CYP2D6 inhibitor Monitor PR and BP at least weekly until stable. Warn patients to report symptoms of hypotension (lightheadedness, dizziness on standing, etc.). Consider alternative acid-suppression therapy... 

IMATINIB 1. ANTIARRHYTHMICS -flecainide, mexiletine, propafenone 2. ANTIDEPRESSANTS - fluoxetine, paroxetine, TCAs, trazodone, venlafaxine 3. ANTIPSYCHOTICS -clozapine, haloperidol, perphenazine, risperidone, thioridazine 4. BETA-BLOCKERS - metoprolol, propanolol, timolol 5. DONEPEZIL 6. METHAMPHETAMINE Imatinib may cause t plasma concentrations of these drugs, with a risk of toxic effects Inhibition of CYP2D6-mediated metabolism of these drugs Watch for early features of toxicity of these drugs... 

An interaction of lidocaine with mexiletine, which resulted in toxic concentrations of lidocaine, has been reported (79). 

FIG. 5. Use-dependent inhibition of fast Na" current in GH-3 cells. (A) Tonically inhibited current (measured at 0.1 Hz frequency) is further decreased, to a new steady-state, by a train of 20,1 s long depolarizations to 0 mV applied at 10 Hz. (B) Mexiletine s concentration-dependent role in steady-state use-dependent inhibition is shown by binding curves with inhibitory dissociation constants (Kj) that differ fourfold between enantiomers. Cumulative, endogenous slow inactivation accounts for the 15-20% reduction of current observed at 10 Hz without drugs. (C) The steady-state inhibition by M reached at 10 Hz stimulation frequency is still further potentiated when the potential between depolarizations is held at — 60 mV. 

In contrast to caffeine, propafenone coadministration significantly reduced the metabolism of both enantiomers of mexiletine in EMs [132]. However, it did not have a significant effect on the pharmacokinetics of mexiletine enantiomers in PMs. In fact, after coadministration of propafenone to EMs, the plasma concentration-time profiles and pharmacokinetics of mexiletine enantiomers in these subjects were not distinguishable from those in PMs [132]. These results are in agreement with the inhibitory effects of propafenone on the CYP2D6 pathway and are similar to those obtained with quinidine, another CYP2D6 inhibitor (Table 13). 

The antacid almasilate (Gelusil), given one hour before a single 400-mg dose of mexiletine, resulted in a slight delay in absorption (time to maximum concentration prolonged from 1.7 to 2.9 hours), but had no effect on the extent of absorption in healthy subjects. ... 

A crossover study in 9 healthy Japanese men found that when they were given mexiletine 200 mg after taking omeprazole 40 mg daily for 8 days, the mexiletine serum concentrations and its AUCs remained unchanged. It was concluded that omeprazole does not affect the metabolism of mexiletine, and no special precautions would seem to be needed if these drugs are used concurrently. 

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