Elsherbiny Marwa E, El-Kadi Ayman O S, Brocks Dion R
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta.
J Pharm Pharm Sci. 2008;11(1):147-59. doi: 10.18433/j3sg66.
To evaluate the metabolism of amiodarone (AM) to desethylamiodarone (DEA) by selected human and rat cytochrome P450, and the inhibitory effect of ketoconazole (KTZ).
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.
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.
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.
通过选定的人和大鼠细胞色素P450评估胺碘酮（AM）向去乙基胺碘酮（DEA）的代谢情况，以及酮康唑（KTZ）的抑制作用。
将不同浓度的AM加入一些重要的CYP同工酶（大鼠CYP1A1、1A2、2C6、2C11、2D1、2D2和3A1以及人CYP1A1、1A2、2D6和3A4）中，以确定在存在和不存在不同浓度KTZ的情况下形成DEA的相对动力学参数。
当AM与每种测试的CYP接触时，均观察到DEA的形成，尽管速率有所不同。人CYP1A1随后是3A4对DEA形成具有最高的内在清除率（CLint），而在大鼠中，CYP2D1随后是CYP2C11具有最高的CLint。人和大鼠的CYP1A2似乎具有最低的CLint。在高浓度的AM和KTZ下，接近体内预期浓度时，观察到除大鼠CYP1A2外所有同工酶均受到显著抑制。在两种药物的较低浓度范围内，测定了抑制常数。在这些水平下，发现KTZ能有效抑制人CYP1A1和3A4以及大鼠2D2和1A1。
人CYP1A1和3A4以及大鼠CYP2D1和2C11在将AM转化为DEA方面效率最高。对于DEA的形成，体内给予KTZ除了能抑制人和大鼠中的CYP3A外，还能抑制其他CYP同工酶。
