Tizanidine is mainly metabolized by cytochrome p450 1A2 in vitro

Aims: To identify the Cytochrome P450 (CYP) enzyme(s) that catalyze the metabolism of tizanidine in vitro.

Methods: The effect of CYP isoform inhibitors on the elimination of tizanidine was studied using pooled human liver microsomes. The metabolism of the drug by a range of human recombinant CYP isoforms was then investigated.

Results: Incubation of tizanidine (80 nm) with human liver microsomes resulted in time- and NADPH-dependent substrate consumption with a half-life of 50 min, initial reaction velocity of 1.1 pmol x min-1 x mg-1 protein and intrinsic clearance of 17 ml x min-1 x kg-1. The predicted in vivo hepatic clearance (CLh) of tizanidine using the well-stirred and parallel-tube model was close (68% and 82%, respectively) to its estimated in vivo CLh. Fluvoxamine and furafylline strongly inhibited tizanidine metabolism. Inhibitors specific to isoforms Other than CYP1A2 had no substantial effect. Recombinant CYP1A2 metabolized tizanidine to a substantial degree (35% in 45 min), but Other recombinant CYPs had little metabolic capacity for the drug.

Conclusions: CYP1A2 is primarily responsible for the metabolism of tizanidine. CYP1A2 inhibitors may inhibit its metabolism also in vivo.