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 min⁻¹ mg⁻¹ protein and intrinsic clearance of 17 ml min⁻¹ kg⁻¹. The predicted in vivo hepatic clearance (CL_h) of tizanidine using the well-stirred and parallel-tube model was close (68% and 82%, respectively) to its estimated in vivo CL_h. 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.