title: Identification of CYP3A4 as the primary cytochrome P450 responsible for the metabolism of tandospirone by human liver microsomes.
abstract: The present study was carried out to characterize the human P450 isoforms involved in the metabolism of tandospirone, an anxiolytic agent known for its superior efficacy and safety. Among 11 yeast-expressed recombinant P450 isoforms tested, CYP2D6 and CYP3A4 exhibited the highest tandospirone metabolic activity. Although there was no qualitative difference between the two isoforms, a quantitative difference in metabolite profiling was found i.e., M4 (hydroxylation of the pyrimidine ring) was the major metabolite formed with CYP2D6 while M2 (hydroxylation of the norbornan ring) and 1-PP (oxidative cleavage of the butyl chain) predominated with CYP3A4. The metabolite profile on incubation with CYP3A4 was qualitatively and quantitatively similar to that obtained with human liver microsomes. In vitro intrinsic clearance (CLint) values derived from kinetic analysis using both P450 isoforms were similar (2.2 and 1.6 ml/min/nmol P450), but the hepatic content of CYP3A4 was found to be more abundant than that of CYP2D6. The in vitro metabolism of tandospirone by human liver microsomes was markedly inhibited by ketoconazole (a CYP3A4 inhibitor) but not by quinidine (a CYP2D6 inhibitor). These results indicate that the metabolism of tandospirone by human liver microsomes primarily involves CYP3A4, and to a lesser extent CYP2D6.
authors.affiliation: Pharmacokinetics Research Laboratories, Dainippon Sumitomo Pharma Co. Ltd, Osaka, Japan.
authors.forename: Kiyohi
authors.initials: K
authors.lastname: Natsui
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Mizuno
authors.forename: Naoko
authors.initials: N
authors.lastname: Tani
authors.forename: Masashi
authors.initials: M
authors.lastname: Yabuki
authors.forename: Setsuko
authors.initials: S
authors.lastname: Komuro
mesh_terms: D014151:Anti-Anxiety Agents / Q000378:metabolism*; D002250:Carbon Radioisotopes; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D065692:Cytochrome P-450 CYP3A Inhibitors; D006801:Humans; D066298:In Vitro Techniques; D054833:Isoindoles / Q000378:metabolism*; D007654:Ketoconazole / Q000494:pharmacology; D008862:Microsomes, Liver / Q000378:metabolism*; D010879:Piperazines / Q000378:metabolism*; D011743:Pyrimidines / Q000378:metabolism*; D011802:Quinidine / Q000494:pharmacology; D011994:Recombinant Proteins / Q000378:metabolism
chemical_list: D014151:Anti-Anxiety Agents; D002250:Carbon Radioisotopes; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D065692:Cytochrome P-450 CYP3A Inhibitors; D054833:Isoindoles; D010879:Piperazines; D011743:Pyrimidines; D011994:Recombinant Proteins; C055267:tandospirone; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D011802:Quinidine; D007654:Ketoconazole