A significant role of human cytochrome P450 2C8 in amiodarone N-deethylation: an approach to predict the contribution with relative activity factor.

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Ohyama K, Nakajima M, Nakamura S, Shimada N, Yamazaki H, Yokoi T

A significant role of human cytochrome P450 2C8 in amiodarone N-deethylation: an approach to predict the contribution with relative activity factor.

Drug Metab Dispos. 2000 Nov;28(11):1303-10.

PubMed ID

11038157 [ View in PubMed

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Abstract

Human cytochrome P450 (CYP) isoforms involved in amiodarone N-deethylation were identified, and the relative contributions of these CYP isoforms were evaluated in different human liver microsomes. The mean K(M) and V(max) values of amiodarone N-deethylation in microsomes from six human livers were 31.6 +/- 7.5 microM 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 microM. 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 microM was significantly correlated with the paclitaxel 6alpha-hydroxylase activity (r = 0.84, P <.05) in the human liver microsomes, whereas the amiodarone N-deethylase activity at 100 microM was significantly correlated with the testosterone 6beta-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.

DrugBank Data that Cites this Article

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Amiodarone	Cytochrome P450 2C19	Protein	Humans	Unknown	Substrate Inhibitor	Details
Amiodarone	Cytochrome P450 2C8	Protein	Humans	No	Substrate	Details
Amiodarone	Cytochrome P450 3A4	Protein	Humans	No	Substrate Inhibitor	Details