RT Journal Article
SR Electronic
T1 Sertraline <em>N</em>-Demethylation Is Catalyzed by Multiple Isoforms of Human Cytochrome  P-450 In Vitro
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 763
OP 766
VO 27
IS 7
A1 Kobayashi, Kaoru
A1 Ishizuka, Tomoko
A1 Shimada, Noriaki
A1 Yoshimura, Yoshitaka
A1 Kamijima, Kunitoshi
A1 Chiba, Kan
YR 1999
UL http://dmd.aspetjournals.org/content/27/7/763.abstract
AB Sertraline, a new antidepressant of the selective serotonin reuptake inhibitor class, is extensively metabolized to desmethylsertraline in humans. We identified the cytochrome P-450 (CYP) isoforms involved in sertraline N-demethylation using pooled human liver microsomes and cDNA-expressed CYP isoforms. Eadie-Hofstee plots for the sertraline N-demethylation in human liver microsomes were monophasic. The estimated Michaelis-Menten kinetic parameters were:KM = 18.1 ± 2.0 μM,Vmax = 0.45 ± 0.03 nmol/min/mg of protein, andVmax/KM = 25.2 ± 4.3 μl/min/mg of protein. At the substrate concentration of 20 μM, which approximated the apparentKM value, sulfaphenazole (CYP2C9 inhibitor) and triazolam (CYP3A substrate) reduced theN-demethylation activities by 20 to 35% in human liver microsomes, whereas the inhibition induced by mephenytoin (CYP2C19 substrate) or quinidine (CYP2D6 inhibitor) was marginal. The anti-CYP2B6 antibody inhibited the sertralineN-demethylation activities by 35%. SertralineN-demethylation activities were detected in all cDNA-expressed CYP isoforms studied. In particular, CYP2C19, CYP2B6, CYP2C9-Arg, CYP2D6-Val, and CYP3A4 all showed relatively high activity. When the contributions of CYP2D6, CYP2C9, CYP2B6, CYP2C19, and CYP3A4 were estimated from theVmax/KM of cDNA-expressed CYP isoforms and from their contents in pooled human liver microsomes, the values were found to be 35, 29, 14, 13, and 9%, respectively. The results suggest that at least five isoforms of CYP (CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A4) are involved in the sertraline N-demethylation in human liver microsomes and that the contribution of any individual isoform does not exceed 40% of overall metabolism. Therefore, concurrent administration of a drug that inhibits a specific CYP isoform is unlikely to cause a marked increase in the plasma concentration of sertraline. The American Society for Pharmacology and Experimental Therapeutics