Inhibition of CYP3A7 DHEA-S Oxidation by Lopinavir and Ritonavir: An Alternative Mechanism for Adrenal Impairment in HIV Antiretroviral-Treated Neonates.
Inhibition of CYP3A7 DHEA-S Oxidation by Lopinavir and Ritonavir: An Alternative Mechanism for Adrenal Impairment in HIV Antiretroviral-Treated Neonates.
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DOI：
10.1021/acs.chemrestox.1c00028
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发表时间：
2021-04-19
影响因子：
4.1
通讯作者：
Lampe JN
中科院分区：
文献类型：
--
作者：
Kandel SE;Lampe JN
对感染艾滋病毒的孕妇及其新生儿进行预防性抗逆转录病毒治疗（ART）可以显著减少母婴病毒传播和新生儿血清转化。利托那韦增强的洛匹那韦方案（称为Kaletra）与早产和新生儿短暂性肾上腺功能不全有关，伴有血浆脱氢表雄酮3-硫酸酯（DHEA-S）增加。在胎儿和新生儿中，细胞色素P450 CYP3A7负责将DHEA-S代谢为16 α-羟基DHEA-S，其在生长和发育中起关键作用。为了确定CYP3A7抑制是否会导致与Kaletra治疗相关的不良结果，我们进行了体外代谢研究，以确定利托那韦和洛匹那韦对CYP3A7的抑制程度和机制，以及洛匹那韦与利托那韦联合和不联合使用时在新生儿和成人肝微粒体（HLM）中的相对固有清除率。我们发现利托那韦是DHEA-S的CYP3A7氧化的强效抑制剂（IC50 = 0.0514 μ M），而洛匹那韦是一种弱得多的抑制剂（IC50 = 5.88 μ M）。此外，利托那韦是一种时间依赖性的CYP3A7抑制剂，KI为0.392 μ M，kinact为0.119 min-1，表明与Kaletra可能存在CYP3A介导的药物相互作用。洛匹那韦在新生儿HLM中的清除率要慢得多，与利托那韦存在下在成人HLM中观察到的清除率相当，这表明在鸡尾酒疗法中添加利托那韦可能不是维持新生儿中洛匹那韦有效浓度所必需的。我们的研究结果表明，Kaletra治疗的几个观察到的不良结果可能是由于利托那韦对CYP3A7的直接抑制，并且在新生儿肝脏中洛匹那韦的清除率较低可能会避免将该药物纳入治疗的必要性。这些结果可能导致重新考虑利托那韦在新生儿抗逆转录病毒治疗中的应用。
Prophylactic antiretroviral therapy (ART) in HIV infected pregnant mothers and their newborns can dramatically reduce mother-to-child viral transmission and seroconversion in the neonate. The ritonavir-boosted lopinavir regimen, known as Kaletra, has been associated with premature birth and transient adrenal insufficiency in newborns, accompanied by increases in plasma dehydroepiandrosterone 3-sulfate (DHEA-S). In the fetus and neonates, cytochrome P450 CYP3A7 is responsible for the metabolism of DHEA-S into 16α-hydroxy DHEA-S, which plays a critical role in growth and development. In order to determine if CYP3A7 inhibition could lead to the adverse outcomes associated with Kaletra therapy, we conducted in vitro metabolic studies to determine the extent and mechanism of CYP3A7 inhibition by both ritonavir and lopinavir and the relative intrinsic clearance of lopinavir with and without ritonavir in both neonatal and adult human liver microsomes (HLMs). We identified ritonavir as a potent inhibitor of CYP3A7 oxidation of DHEA-S (IC50 = 0.0514 μM), while lopinavir is a much weaker inhibitor (IC50 = 5.88 μM). Furthermore, ritonavir is a time-dependent inhibitor of CYP3A7 with a KI of 0.392 μM and a kinact of 0.119 min–1, illustrating the potential for CYP3A mediated drug–drug interactions with Kaletra. The clearance rate of lopinavir in neonatal HLMs was much slower and comparable to the rate observed in adult HLMs in the presence of ritonavir, suggesting that the addition of ritonavir in the cocktail therapy may not be necessary to maintain effective concentrations of lopinavir in neonates. Our results suggest that several of the observed adverse outcomes of Kaletra therapy may be due to the direct inhibition of CYP3A7 by ritonavir and that the necessity for the inclusion of this drug in the therapy may be obviated by the lower rate of lopinavir clearance in the neonatal liver. These results may lead to a reconsideration of the use of ritonavir in neonatal antiretroviral therapy.
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影响因子：
3.2
作者：
Kariyawasam, D.;Simon, A.;Polak, M.
通讯作者：
Polak, M.
影响因子：
3.6
作者：
Hines, Ronald N.
通讯作者：
Hines, Ronald N.
DOI：
10.1016/j.jsbmb.2016.02.002
发表时间：
2017-01
期刊：
The Journal of steroid biochemistry and molecular biology
影响因子：
--
作者：
Auchus RJ
通讯作者：
Auchus RJ
影响因子：
3.6
作者：
Bolt, RJ;Van Weissenbruch, MM;Delemarre-van de Waal, HA
通讯作者：
Delemarre-van de Waal, HA
影响因子：
3
作者：
Kirmse, Brian;Baumgart, Stephen;Rakhmanina, Natella
通讯作者：
Rakhmanina, Natella