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Human cytochromes mediating gepirone biotransformation at low substrate concentrations
Author(s) -
Greenblatt David J.,
von Moltke Lisa L.,
Giancarlo Gina M.,
Garteiz Daniel A.
Publication year - 2003
Publication title -
biopharmaceutics and drug disposition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.419
H-Index - 58
eISSN - 1099-081X
pISSN - 0142-2782
DOI - 10.1002/bdd.340
Subject(s) - chemistry , microsome , cyp3a4 , cyp3a , biotransformation , cytochrome p450 , pharmacology , in vitro , metabolism , biochemistry , enzyme , biology
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. Copyright © 2003 John Wiley & Sons, Ltd.