Effects of cytochrome P450 (CYP) 3A4 inhibitors on the anxiolytic action of tandospirone in rat contextual conditioned fear.
The azapirone derivatives, including tandospirone and buspirone, are anxiolytics with 5-HT(1A) receptor agonistic action. Previous in vitro studies have suggested these azapirone derivatives are mainly metabolized by the cytochrome P450 (CYP) 3A4 isoform. The purpose of this study was to clarify the effects CYP3A4 inhibitors have on the anxiolytic action of tandospirone in a conditioned fear stress rat model. One day after fear conditioning, the orally administered tandospirone (30-100 mg/kg) significantly inhibited conditioned freezing in a dose-dependent manner. Co-administration of oral tandospirone and CYP3A4 inhibitors [ketoconazole (10 mg/kg, i.p.) and cimetidine (200 mg/kg, p.o.)] markedly inhibited conditioned freezing. Ketoconazole significantly increased the anxiolytic effect of buspirone similar to tandospirone. As with freezing behavior, the plasma concentrations of tandospirone and buspirone were increased by CYP3A4 inhibitors. This suggests the CYP3A4 isoform is involved in the metabolism of tandospirone, in vivo. Therefore, drugs with CYP3A4 inhibitory property may facilitate the anxiolytic effect of tandospirone when treating human anxiety disorders.
Nishikawa
Hiroyuki
H
Department of Psychiatry, Hokkaido University Graduate School of Medicine, North 15, West 7, Kita-ku, Sapporo 060-8638, Japan. hnishika@med.hokudai.ac.jp
Inoue
Takeshi
T
Masui
Takuya
T
Izumi
Takeshi
T
Koyama
Tsukasa
T
D000284:Administration, Oral; D000704:Analysis of Variance; D000818:Animals; D014151:Anti-Anxiety Agents / Q000008:administration & dosage* / Q000097:blood; D001007:Anxiety / Q000188:drug therapy; D001522:Behavior, Animal; D002065:Buspirone / Q000008:administration & dosage; D003214:Conditioning, Classical / Q000187:drug effects*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005239:Fear / Q000187:drug effects*; D054833:Isoindoles; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D010879:Piperazines / Q000008:administration & dosage* / Q000097:blood; D011743:Pyrimidines / Q000008:administration & dosage* / Q000097:blood; D051381:Rats; D017207:Rats, Sprague-Dawley
D014151:Anti-Anxiety Agents; D054833:Isoindoles; D010879:Piperazines; D011743:Pyrimidines; C055267:tandospirone; D002065:Buspirone