Comparison of Antifungal Azole Interactions with Adult Cytochrome P450 3A4 versus Neonatal Cytochrome P450 3A7
Comparison of Antifungal Azole Interactions with Adult Cytochrome P450 3A4 versus Neonatal Cytochrome P450 3A7
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DOI：
10.1124/dmd.118.082032
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发表时间：
2018-09-01
影响因子：
3.9
通讯作者：
Scott, Emily E.
中科院分区：
文献类型：
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作者：
Godamudunage, Malika P.;Grech, Anne M.;Scott, Emily E.
成人药物代谢以细胞色素P450 3A 4（CYP 3A 4）为主，而抗真菌唑类药物通常会抑制CYP 3A 4，从而导致药物代谢的潜在改变和药物/药物不良相互作用。在胎儿和新生儿阶段，表达87%相同的细胞色素P450 3A 7（CYP 3A 7），但不表达CYP 3A 4。为成人开发的唑类抗真菌药也用于新生儿，假设它们与两种酶的相互作用相似，但缺乏系统的信息。本文开发了用于产生重组纯化的CYP 3A 7的方法。然后评价13种不同唑类化合物对纯化人CYP 3A 4与CYP 3A 7的结合和抑制。所有含咪唑的唑类通过与血红素铁的配位结合两种酶，并抑制两者，IC 50值范围从克霉唑的180 nM到咪唑本身的毫摩尔范围。在这一广泛的效力范围内，CYP 3A 4的抑制作用始终强于CYP 3A 7，克霉唑是选择性最低（1.5倍）的抑制剂，益康唑选择性最高（12倍）。对含1，2，4-三唑的唑类化合物的观察结果更为多样。大多数通过与血红素铁配位与CYP 3A 4结合，但也有几种在低浓度下表现出不同结合模式的证据。然而，只有泊沙康唑抑制CYP 3A 4。在三唑类药物中，仅泊沙康唑抑制CYP 3A 7，同样效力低于CYP 3A 4。对于所有三唑，结合的光谱证据都很弱或不存在。总体而言，尽管结合相互作用的细节确实不同，但相同的唑类化合物抑制两种酶，尽管与CYP 3A 4相比，与CYP 3A 7的相互作用较弱。
Adult drug metabolism is dominated by cytochrome P450 3A4 (CYP3A4), which is often inhibited by antifungal azole drugs, resulting in potential alterations in drug metabolism and adverse drug/drug interactions. In the fetal and neonatal stages of life, the 87% identical cytochrome P450 3A7 (CYP3A7) is expressed but not CYP3A4. Azole antifungals developed for adults are also used in neonates, assuming they interact similarly with both enzymes, but systematic information is lacking. Herein a method was developed for generating recombinant purified CYP3A7. Thirteen different azoles were then evaluated for binding and inhibition of purified human CYP3A4 versus CYP3A7. All imidazole-containing azoles bound both enzymes via coordination to the heme iron and inhibited both with IC50 values ranging from 180 nM for clotrimazole to the millimolar range for imidazole itself. Across this wide range of potencies, CYP3A4 was consistently inhibited more strongly than CYP3A7, with clotrimazole being the least selective (1.5-fold) inhibitor and econazole the most selective (12-fold). Observations for 1,2,4triazole-containing azoles were more varied. Most bound to CYP3A4 via coordination to the heme iron, but several also demonstrated evidence of a distinct binding mode at low concentrations. However, only posaconazole inhibited CYP3A4. Of the triazoles, only posaconazole inhibited CYP3A7, again less potently than CYP3A4. Spectral evidence for binding was weak or nonexistent for all triazoles. Overall, although the details of binding interactions do vary, the same azole compounds inhibit both enzymes, albeit with weaker interactions with CYP3A7 compared with CYP3A4.