Identification of cytochrome P450 isoform involved in the metabolism of YM992, a novel selective serotonin re-uptake inhibitor, in human liver microsomes.
1. In vitro studies were conducted to identify the hepatic cytochrome P450 isoform involved in the metabolism of YM992, ((S)-2-[[(fluoro-4-indanyl)oxy]methyl]morpholine monohydrochloride), a novel serotonin re-uptake inhibitor, in human liver microsomes. 2. Microsomes prepared from yeast expressing CYP1A1, CYP1A2 and CYP2D6 effectively metabolized YM992. A significant correlation was observed between the rate of YM992 metabolism and 7-ethoxyresorufin O-deethylation, CYP1A1/2 specific activity, in liver microsomes from 16 individual donors (r2 = 0.628, p < 0.001). Alpha-naphtoflavone and isosafrole, CYP1A1/2 inhibitors, suppressed the metabolism of YM992 in human liver microsomes in a concentration-dependent manner. 3. The metabolism of YM992 in human liver microsomes was inhibited by approximately 95% by antibodies which recognize both CYP1A1 and CYP1A2 whereas antibodies specific for CYP1A1 did not show inhibitory effects. 4. The same major metabolites, M6 and M7, were generated from YM992 after incubation with human liver microsomes and recombinant human CYP1A2. 5. These results suggest that the metabolism of YM992 in human liver microsomes is mainly catalysed by CYP1A2, and that YM992 might increase plasma concentration of concomitant drugs metabolized by CYP1A2 due to competitive inhibition.
Noguchi
K
K
Drug Metabolism Laboratories, Yamanouchi Pharmaceuticals Co., Ltd., Tokyo, Japan. noguchik@yamanouchi.co.jp
Mera
A
A
Watanabe
T
T
Higuchi
S
S
Chiba
K
K
D001571:Benzoflavones / Q000378:metabolism; D002845:Chromatography; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry*; D018076:DNA, Complementary / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007700:Kinetics; D008862:Microsomes, Liver / Q000187:drug effects* / Q000378:metabolism*; D008954:Models, Biological; D009025:Morpholines / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics*; D011485:Protein Binding; D020033:Protein Isoforms; D011994:Recombinant Proteins / Q000378:metabolism; D012451:Safrole / Q000378:metabolism; D012702:Serotonin Antagonists / Q000493:pharmacokinetics*; D017367:Selective Serotonin Reuptake Inhibitors / Q000493:pharmacokinetics*
D001571:Benzoflavones; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2; D019389:Cytochrome P-450 CYP2D6; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System; D018076:DNA, Complementary; D009025:Morpholines; D020033:Protein Isoforms; D011994:Recombinant Proteins; D012451:Safrole; D012702:Serotonin Antagonists; D017367:Selective Serotonin Reuptake Inhibitors; C105748:lubazodone hydrochloride; C011512:alpha-naphthoflavone; C015959:isosafrole