PT - JOURNAL ARTICLE AU - Katsuhiro Ohyama AU - Miki Nakajima AU - Sumika Nakamura AU - Noriaki Shimada AU - Hiroshi Yamazaki AU - Tsuyoshi Yokoi TI - A Significant Role of Human Cytochrome P450 2C8 in Amiodarone <em>N</em>-Deethylation: An Approach to Predict the Contribution with Relative Activity Factor DP - 2000 Nov 01 TA - Drug Metabolism and Disposition PG - 1303--1310 VI - 28 IP - 11 4099 - http://dmd.aspetjournals.org/content/28/11/1303.short 4100 - http://dmd.aspetjournals.org/content/28/11/1303.full SO - Drug Metab Dispos2000 Nov 01; 28 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 &lt; .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 &lt; .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