RT Journal Article SR Electronic T1 A Significant Role of Human Cytochrome P450 2C8 in Amiodarone N-Deethylation: An Approach to Predict the Contribution with Relative Activity Factor JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP 1303 OP 1310 VO 28 IS 11 A1 Katsuhiro Ohyama A1 Miki Nakajima A1 Sumika Nakamura A1 Noriaki Shimada A1 Hiroshi Yamazaki A1 Tsuyoshi Yokoi YR 2000 UL http://dmd.aspetjournals.org/content/28/11/1303.abstract AB Human cytochrome P450 (CYP) isoforms involved in amiodaroneN-deethylation were identified, and the relative contributions of these CYP isoforms were evaluated in different human liver microsomes. The mean KM andVmax values of amiodaroneN-deethylation in microsomes from six human livers were 31.6 ± 7.5 μM and 1.2 ± 0.7 pmol/min/pmol of CYP, respectively. Ketoconazole and anti-CYP3A antibodies strongly inhibited amiodarone N-deethylase activity in human liver microsomes at a substrate concentration of 50 μM. Of 15 recombinant human CYP enzymes (19 preparations), CYP1A1, CYP3A4, CYP1A2, CYP2D6, CYP2C8, and CYP2C19 catalyzed amiodarone N-deethylation. The amiodarone N-deethylase activity at a substrate concentration of 5 μM was significantly correlated with the paclitaxel 6α-hydroxylase activity (r = 0.84,P < .05) in the human liver microsomes, whereas the amiodarone N-deethylase activity at 100 μM was significantly correlated with the testosterone 6β-hydroxylase activity (r = 0.94, P < .005). According to the concept of relative activity factor, it was clarified that CYP2C8 as well as CYP3A4 were significantly involved in amiodarone N-deethylation in human livers at clinically significant concentrations and that the contributions of CYP1A2, CYP2C19, and CYP2D6 were relatively minor. However, there was a large interindividual variability in the contribution of each CYP isoform to amiodarone N-deethylase activity in human liver; the relevance of these enzymes would be dependent on the content of the respective isoforms and on the amiodarone concentration in the liver. The American Society for Pharmacology and Experimental Therapeutics