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Tizanidine is mainly metabolized by cytochrome P450 1A2 in vitro
Author(s) -
Granfors Marika T.,
Backman Janne T.,
Laitila Jouko,
Neuvonen Pertti J.
Publication year - 2004
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1046/j.1365-2125.2003.02028.x
Subject(s) - tizanidine , cyp1a2 , microsome , cytochrome p450 , pharmacology , metabolism , chemistry , cyp3a4 , cyp2d6 , drug metabolism , in vivo , biochemistry , enzyme , biology , medicine , microbiology and biotechnology , spasticity , physical therapy
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 n m ) 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 .