Comparison of the inhibitory effects of azole antifungals on cytochrome P450 3A4 genetic variants.
Comparison of the inhibitory effects of azole antifungals on cytochrome P450 3A4 genetic variants.
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唑类抗真菌药对细胞色素P450 3A4遗传变异体抑制作用的比较
DOI：
10.1016/j.dmpk.2021.100384
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发表时间：
2021-06
影响因子：
2.1
通讯作者：
Ohtani H
中科院分区：
文献类型：
--
作者：
Yamaguchi Y;Akiyoshi T;Kawamura G;Imaoka A;Miyazaki M;Guengerich FP;Nakamura K;Yamamoto K;Ohtani H
细胞色素P450(CYP)3A4是主要的药物代谢酶之一。活性改变的CYP3A4基因变异是导致药物代谢个体差异的因素之一。唑类抗真菌药竞争性抑制细胞色素P3A4，导致临床上显著的药物-药物相互作用。在这项定量研究中，我们通过重组CYP3A4基因变异(CYP3A4.1(WT)、CYP3A4.2、CYP3A4.7、CYP3A4.16和CYP3A4.18)研究了三种唑类抗真菌药物(酮康唑、伏立康唑和氟康唑)对睾酮代谢的抑制作用，并与已报道的伊曲康唑进行了比较。酮康唑、伏立康唑和氟康唑对rCYP3A4.1的抑制常数(KI)分别为3.6nM、3.2μM和18.3μM。这些化合物对rCYP3A4.16的Ki值分别是rCYP3A4.1的13.9倍、13.6倍和6.1倍，而伊曲康唑对rCYP3A4.16的Ki值是rCYP3A4.1的0.54倍。其他遗传变异对这三种咪唑的KI值有相似的影响，而伊曲康唑的模式则截然不同。综上所述，伊曲康唑具有与其他唑类抗真菌药物酮康唑、伏立康唑和氟康唑相同的独特特征，即基因变异对细胞色素P3A4抑制的影响。
Cytochrome P450 (CYP) 3A4 is one of the major drug-metabolizing enzymes. Genetic variants of CYP3A4 with altered activity are one of the factors responsible for interindividual differences in drug metabolism. Azole antifungals competitively inhibit CYP3A4 to cause clinically significant drug-drug interactions. In the present quantitative study, we investigated the inhibitory effects of three azole antifungals (ketoconazole, voriconazole, and fluconazole) on testosterone metabolism by recombinant CYP3A4 genetic variants (CYP3A4.1 (WT), CYP3A4.2, CYP3A4.7, CYP3A4.16, and CYP3A4.18) and compared them with those previously reported for itraconazole. The inhibition constants (Ki) of ketoconazole, voriconazole, and fluconazole for rCYP3A4.1 were 3.6 nM, 3.2 μM, and 18.3 μM, respectively. The Ki values of these azoles for rCYP3A4.16 were 13.9-, 13.6-, and 6.1-fold higher than those for rCYP3A4.1, respectively, whereas the Ki value of itraconazole for rCYP3A4.16 was 0.54-fold of that for rCYP3A4.1. The other genetic variants had similar effects on the Ki values of the three azoles, whereas a very different pattern was seen for itraconazole. In conclusion, itraconazole has unique characteristics that are distinct from those shared by the other azole anti-fungal drugs ketoconazole, voriconazole, and fluconazole with regard to the influence of genetic variations on the inhibition of CYP3A4.
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影响因子：
3.9
作者：
GILLAM, EMJ;BABA, T;GUENGERICH, FP
通讯作者：
GUENGERICH, FP
影响因子：
1.8
作者：
Gibson, C. R.;Bergman, A.;Mulrooney, E.
通讯作者：
Mulrooney, E.
DOI：
10.1097/00008571-200107000-00008
发表时间：
2001-07-01
期刊：
PHARMACOGENETICS
影响因子：
--
作者：
Eiselt, R;Domanski, TL;Wojnowski, L
通讯作者：
Wojnowski, L
影响因子：
2.9
作者：
vonMoltke, LL;Greenblatt, DJ;Shader, RI
通讯作者：
Shader, RI
影响因子：
4.9
作者：
VANDENBOSSCHE, H;MARICHAL, P;JANSSEN, PAJ
通讯作者：
JANSSEN, PAJ