Effects of mexiletine, a CYP1A2 inhibitor, on tizanidine pharmacokinetics and pharmacodynamics.
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.
Department of Pharmaceutical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Ibaraki, Japan.
Kenji
K
Momo
Masato
M
Homma
Yoshiko
Y
Osaka
Shin-ichi
S
Inomata
Makoto
M
Tanaka
Yukinao
Y
Kohda
D000328:Adult; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001794:Blood Pressure / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D003000:Clonidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004347:Drug Interactions; D006207:Half-Life; D006801:Humans; D008297:Male; D008801:Mexiletine / Q000494:pharmacology*; D012894:Sleep Stages / Q000187:drug effects; D053719:Tandem Mass Spectrometry; D014987:Xerostomia / Q000139:chemically induced / Q000188:drug therapy
D000889:Anti-Arrhythmia Agents; D000959:Antihypertensive Agents; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D008801:Mexiletine; C023754:tizanidine; D003000:Clonidine