The metabolism of amiodarone by various CYP isoenzymes of human and rat, and the inhibitory influence of ketoconazole

Abstract

-PURPOSE. To evaluate the metabolism of amiodarone (AM) to desethylamiodarone (DEA) by selected human and rat cytochrome P450, and the inhibitory effect of ketoconazole (KTZ). METHODS. Some important CYP isoenzymes (rat CYP1A1, 1A2, 2C6, 2C11, 2D1, 2D2, and 3A1 and human CYP1A1, 1A2, 2D6 and 3A4) were spiked with various concentrations of AM to determine the relative kinetic parameters for formation of DEA in the presence and absence of various concentrations of KTZ. RESULTS. The formation of DEA was observed when AM was exposed to each of the CYP tested, although the rates were varied. Human CYP1A1 followed by 3A4 had the highest intrinsic clearance (CLint) for DEA formation whereas in rat, CYP2D1 followed by CYP2C11 had the highest CLint. Human and rat CYP1A2 seemed to have the lowest CLint. At high concentrations of AM and KTZ, near those expected in vivo, significant inhibition of all isoforms except for rat CYP1A2 was observed. At lower concentration ranges of both drugs, the inhibitory constant was determined. At these levels, KTZ was found to potently inhibit human CYP1A1 and 3A4 and rat 2D2 and 1A1. CONCLUSION. Human CYP1A1 and 3A4 and rat CYP2D1 and 2C11 were most efficient in converting AM to DEA. For DEA formation, the in vivo administration of KTZ could inhibit other CYP isoforms besides CYP3A in human and rat.

Changes in cytochrome P450 gene expression and enzyme activity induced by xenobiotics in rabbits in vivo and in vitro

“…Our findings are in accordance with Korashy et al (Korashy et al, 2007) where ketoconazole was found to induce CYP1A1 at the transcriptional and protein level in human and murine cell lines. Others have found that ketoconazole is an effective CYP1A1 inhibitor in humans (Paine et al, 1999) and rats (Elsherbiny et al, 2008); our experiments are concordant, showing that ketoconazole is also a highly effective inhibitor of rabbit CYP1A1, in vitro. In our study, ketoconazole had opposite effects at the transcriptional and protein levels on CYP450 enzymes, in vitro.…”

Development of HepG2-derived cells expressing cytochrome P450s for assessing metabolism-associated drug-induced liver toxicity

“…A high ratio of DEA/aminodarone in the plasma and liver is considered as a risk factor for hepatotoxicity [54]. There is evidence demonstrating that CYP1A1 and CYP3A4 are the most efficient enzymes transforming amiodarone to DEA and the former isoform has higher potency [55], which is consistent with the results of our cytotoxicity assays. Several other CYP isoforms, including CYP1A2, CYP2C8, CYP2C19, and CYP2D6, have also been involved in DEA production in humans, but we found that the overexpression of these metabolizing enzymes did not increase but even decreased the cytotoxicity of amiodarone, suggesting that they may contribute, even more significantly, in the detoxification of DEA.…”

Evaluation of a general toxicity study incorporating phototoxicity assessments in Sprague-Dawley rats

“…However, further studies are needed in order to confirm that this toxicity evaluation method can also be used to evaluate drugs with accumulative properties, like meloxicam (Seto et al, 2013;Türck et al, 1997), or that are degraded by metabolic enzymes, like amiodarones (Allen, 1993;Elsherbiny et al, 2008;Yonezawa et al, 2015). These drugs may affect the TK parameters throughout the dosing period, and may cause different phototoxic reactions between the first administration and final administration.…”