title: [Effect of tofisopam on CYP3A4 enzyme activity on human recombinant 3A4 supersome].
abstract: Tofisopam is an anxiolytic agent of the BZD group, chemically 1(3-4 dimethoxyphenyl)-4methyl-5-ethyl-7,8 dimethoxy-5H-2,3-benzodiazepine. TZP differs from the traditional 1,4-benzodiazepines regarding the positions of the nitrogen atoms. Three clinical cases were reported where tofisopam increased the blood level of immunosuppressive agent leading clinically relevant adverse drug reaction and necessitating reduction of the dose of the drugs or discontinuation of the administration of tofisopam. The administered immunosuppressive agent is a substrate of the CYP3A4 system, so the effect of tofisopam on the CYP3A4 enzyme was investigated in vitro using human recombinant CYP3A4 supersome. Benzyoxy-4-(trifluoromethyl)-coumarin (BFC) was used as substrate. Tofisopam in 0.1, 0.25, 0.5, 0.75, 1 and 5 micromol/l concentrations inhibited dose dependently the enzyme activity. Activity inhibition rates were 4%, 29%, 40%, 56%, 61% and 94%, respectively and the IC50 was 0.8 micromol/l. The IC50 of positive control substance ketoconazole was 0.03 micromol/l. In in vitro experiments the inhibitory effect of tofisopam was lower than that of ketoconazole (potent CYP3A4 inhibitor) with an order of magnitude. According to the in vitro results it could be concluded that tofisopam is an inhibitor of CYP3A4 but to clarify the clinical importance of this inhibition further human clinical data are needed.
authors.affiliation: EGIS Gyógyszergyár Rt., Klinikai Kutatási Csoport, Budapest.
authors.forename: Mária
authors.initials: M
authors.lastname: Tóth
authors.forename: Judit
authors.initials: J
authors.lastname: Bajnógel
authors.forename: András
authors.initials: A
authors.lastname: Egyed
authors.forename: Sándor
authors.initials: S
authors.lastname: Drabant
authors.forename: Judit
authors.initials: J
authors.lastname: Tömlo
authors.forename: Imre
authors.initials: I
authors.lastname: Klebovich
mesh_terms: D000928:Antidepressive Agents / Q000494:pharmacology; D001569:Benzodiazepines / Q000494:pharmacology*; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007654:Ketoconazole / Q000494:pharmacology; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors
chemical_list: D000928:Antidepressive Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D011994:Recombinant Proteins; D001569:Benzodiazepines; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D007654:Ketoconazole; C012582:tofisopam