Effects of Mexiletine, a CYP1A2 Inhibitor, on Tizanidine Pharmacokinetics and Pharmacodynamics

Abstract

The aim of our study is to determine whether mexiletine, a CYP1A2 inhibitor, altered the pharmacokinetics and pharmacodynamics of tizanidine. Pharmacokinetics of tizanidine was examined in an open-label study in 12 healthy subjects after a single dose of tizanidine (2 mg) with and without mexiletine coadministration (50 mg, 3 times as a pre-treatment 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•h/mL) and the half-life (1.3 ± 0.2 vs. 1.8 ± 0.7 h) of tizanidine, respectively (P<0.05). Reduction in systolic blood pressure (−10 ± 8 vs. −24 ± 7 mmHg) and diastolic blood pressure (−10 ± 7 vs. −18 ± 8 mmHg) after tizanidine administration were also significantly enhanced by coadministration of mexiletine (P<0.01). 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.3

A severe tremor caused by a beta2 agonist in a patient with asthma‐chronic obstructive pulmonary disease overlap

“…To assess the recurrence of tremors after stopping tizanidine, we conducted a spiral writing test on Day 122. Considering the half‐life of tizanidine is ~1.5 h, 12 we believe that the effects of tizanidine completely disappeared by Day 122, which was 29 days after drug discontinuation, and there was no recurrence of symptoms. Therefore, we did not conduct further evaluations in the current case.…”

“…However, it is essential to note that tizanidine is metabolized solely by the drug‐metabolizing CYP1A2 enzyme, posing a potential risk for severe drug–drug interactions, especially in polypharmacy patients. 12 , 15 , 16 , 17 , 18 , 19 The use of tizanidine for the management of tremors requires further investigation and careful consideration. We have previously reported a case demonstrating severe symptoms resulting from the combination of tizanidine 16 , 17 and a CYP1A2 inhibitor.…”

Development and validation of a reverse phase high performance liquid chromatography (HPLC) method for determination of tizanidine in human plasma

“…(Lee et al, 2002). Momo et al (2010) determined tizanidine in human plasma and urine with use of liquid chroma-tography-tandem mass spectrometry in presence of maxiletine (Momo et al, 2010). Ulu et al (2012) utilized a spectroflourimetric method based on dervitization for estimation of tizanidine in plasma, urine and dosage forms (Ulu et al, 2012).…”

Thermoreversible Switchlike Electrocatalytic Reduction of Tizanidine Based on a Graphene Oxide Tethered Stimuli-Responsive Smart Surface Supported Pd Catalyst

“…Many researchers have reported on the determination of TZN in human urine and plasma samples. Momo et al have determined TZN in human plasma and urine through use of liquid chromatography-tandem mass spectrometry . Ulu used a spectroflourimetric determination method for the estimation of plasma (detection limit: 1.81 ng/mL), urine (detection limit: 0.54 ng/mL), and tablet samples .…”

“…Momo et al have determined TZN in human plasma and urine through use of liquid chromatography-tandem mass spectrometry. 33 Ulu used a spectroflourimetric determination method for the estimation of plasma (detection limit: 1.81 ng/mL), urine (detection limit: 0.54 ng/ mL), and tablet samples. 34 Therefore, selective detection of TZN in relevant samples are still needed.…”