Effects of mexiletine, a CYP1A2 inhibitor, on tizanidine pharmacokinetics and pharmacodynamics

J Clin Pharmacol. 2010 Mar;50(3):331-7. doi: 10.1177/0091270009341961. Epub 2009 Sep 29.

Abstract

The aim of this study was to determine whether mexiletine, a CYP1A2 inhibitor, altered the pharmacokinetics and pharmacodynamics of tizanidine. The pharmacokinetics of tizanidine were examined in an open-label study in 12 healthy participants after a single dose of tizanidine (2 mg) with and without mexiletine coadministration (50 mg, 3 times as a pretreatment for a day and 2 times on the study day). Compared with tizanidine alone, mexiletine coadministration increased the peak plasma concentration (1.8 +/- 0.8 vs 5.3 +/- 1.8 ng/mL), area under the curve (4.5 +/- 2.2 vs 15.4 +/- 6.5 ng x h/mL), and the half-life (1.3 +/- 0.2 vs 1.8 +/- 0.7 h) of tizanidine, respectively (P < .05). Reduction in systolic blood pressure (-10 +/- 8 vs -24 +/- 7 mm Hg) and diastolic blood pressure (-10 +/- 7 vs -18 +/- 8 mm Hg) after tizanidine administration was also significantly enhanced by coadministration of mexiletine (P < .01). Of the 15 patients treated with tizanidine and mexiletine, 4 suffered tizanidine-induced adverse effects such as drowsiness and dry mouth in the retrospective survey. Present results suggested that coadministration of mexiletine increased blood tizanidine concentrations and enhanced tizanidine pharmacodynamics in terms of reduction in blood pressure and adverse symptoms.

Publication types

  • Clinical Trial
  • Comparative Study

MeSH terms

  • Adult
  • Anti-Arrhythmia Agents / pharmacology*
  • Antihypertensive Agents / administration & dosage
  • Antihypertensive Agents / adverse effects
  • Antihypertensive Agents / blood
  • Antihypertensive Agents / pharmacokinetics*
  • Area Under Curve
  • Blood Pressure / drug effects
  • Chromatography, High Pressure Liquid
  • Clonidine / administration & dosage
  • Clonidine / adverse effects
  • Clonidine / analogs & derivatives*
  • Clonidine / blood
  • Clonidine / pharmacokinetics
  • Cytochrome P-450 CYP1A2 Inhibitors*
  • Dose-Response Relationship, Drug
  • Drug Administration Schedule
  • Drug Interactions*
  • Half-Life
  • Humans
  • Male
  • Mexiletine / pharmacology*
  • Sleep Stages / drug effects
  • Tandem Mass Spectrometry
  • Xerostomia / chemically induced
  • Xerostomia / drug therapy

Substances

  • Anti-Arrhythmia Agents
  • Antihypertensive Agents
  • Cytochrome P-450 CYP1A2 Inhibitors
  • Mexiletine
  • tizanidine
  • Clonidine