title: Human cytochromes mediating gepirone biotransformation at low substrate concentrations.
abstract: Biotransformation of gepirone to 1-(2-pyrimidinyl)-piperazine (1-PP) and 3'-OH-gepirone, as well as two other hydroxylated metabolites, was studied in vitro using a human liver microsomal preparation and heterologously expressed human CYP3A4 and CYP2D6. The focus was on a low range of gepirone concentrations (1000 nM and below). Liver microsomes formed 1-PP and 3'-OH-gepirone with similar reaction velocities. Two other hydroxylated metabolites (2-OH- and 5-OH-gepirone) were also formed, but pure reference standards were not available for purposes of quantitative analysis. The CYP3A inhibitor ketoconazole completely eliminated 1-PP formation, reduced 3'-OH-gepirone formation to less than 20% of control, and reduced 2-OH-gepirone formation to 7% of control. All metabolites were formed by expressed CYP3A4; however, CYP2D6 formed 3'-OH- and 5-OH-gepirone, but not 1-PP or 2-OH-gepirone. Based on estimated relative abundances of the two isoforms in human liver, CYP3A4 was predicted to account for more than 95% of net clearance of gepirone in vivo at low concentrations approaching the therapeutic range. CYP2D6 would account for less than 5% of net clearance. The findings are consistent with previous in vitro studies of gepirone using higher substrate concentrations.
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Tufts-New England Medical Center, Boston MA 02111, USA. dj.greenbalt@tufts.edu
authors.forename: David J
authors.initials: DJ
authors.lastname: Greenblatt
authors.forename: Lisa L
authors.initials: LL
authors.lastname: Von Moltke
authors.forename: Gina M
authors.initials: GM
authors.lastname: Giancarlo
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Garteiz
mesh_terms: D001711:Biotransformation; D002065:Buspirone / Q000031:analogs & derivatives* / Q000378:metabolism; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism*; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D066298:In Vitro Techniques; D008862:Microsomes, Liver / Q000378:metabolism; D010881:Piperidones / Q000378:metabolism; D011743:Pyrimidines / Q000378:metabolism / Q000493:pharmacokinetics*; D017366:Serotonin Receptor Agonists / Q000378:metabolism / Q000493:pharmacokinetics*
chemical_list: C478009:2-hydroxygepirone; C478008:3'-hydroxygepirone; C478010:5-hydroxygepirone; D010881:Piperidones; D011743:Pyrimidines; D017366:Serotonin Receptor Agonists; D003577:Cytochrome P-450 Enzyme System; C104464:CYP3A protein, human; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; C037921:1-(2-pyrimidinyl)piperazine; C039979:gepirone; D002065:Buspirone