Department of Pharmacology and Experimental Neuroscience (J.M.M., D.A.C., M.G.B., R.S.D., A.A.B.W., W.W., E.M., T.K., P.S.J., H.E.G., S.G., L.Y.P.), Developmental Neuroscience, Munroe Meyer Institute for Genetics and Rehabilitation (C.B.G.), Department of Pharmaceutical Sciences (Z.L.), Mouse Genome Engineering Core Facility, Vice Chancellor for Research Office (R.M.Q., D.W.H., C.B.G.), and Department of Pathology and Microbiology (S.M.C.), University of Nebraska Medical Center, Omaha, Nebraska
Department of Pharmacology and Experimental Neuroscience (J.M.M., D.A.C., M.G.B., R.S.D., A.A.B.W., W.W., E.M., T.K., P.S.J., H.E.G., S.G., L.Y.P.), Developmental Neuroscience, Munroe Meyer Institute for Genetics and Rehabilitation (C.B.G.), Department of Pharmaceutical Sciences (Z.L.), Mouse Genome Engineering Core Facility, Vice Chancellor for Research Office (R.M.Q., D.W.H., C.B.G.), and Department of Pathology and Microbiology (S.M.C.), University of Nebraska Medical Center, Omaha, Nebraska.
J Pharmacol Exp Ther. 2018 May;365(2):272-280. doi: 10.1124/jpet.117.247288. Epub 2018 Feb 23.
Antiretroviral drug (ARV) metabolism is linked largely to hepatic cytochrome P450 activity. One ARV drug class known to be metabolized by intestinal and hepatic CYP3A are the protease inhibitors (PIs). Plasma drug concentrations are boosted by CYP3A inhibitors such as cobisistat and ritonavir (RTV). Studies of such drug-drug interactions are limited since the enzyme pathways are human specific. While immune-deficient mice reconstituted with human cells are an excellent model to study ARVs during human immunodeficiency virus type 1 (HIV-1) infection, they cannot reflect human drug metabolism. Thus, we created a mouse strain with the human pregnane X receptor, constitutive androstane receptor, and CYP3A4/7 genes on a NOD.Cg- /JicTac background (hCYP3A-NOG) and used them to evaluate the impact of human CYP3A metabolism on ARV pharmacokinetics. In proof-of-concept studies we used nanoformulated atazanavir (nanoATV) with or without RTV. NOG and hCYP3A-NOG mice were treated weekly with 50 mg/kg nanoATV alone or boosted with nanoformulated ritonavir (nanoATV/r). Plasma was collected weekly and liver was collected at 28 days post-treatment. Plasma and liver atazanavir (ATV) concentrations in nanoATV/r-treated hCYP3A-NOG mice were 2- to 4-fold higher than in replicate NOG mice. RTV enhanced plasma and liver ATV concentrations 3-fold in hCYP3A-NOG mice and 1.7-fold in NOG mice. The results indicate that human CYP3A-mediated drug metabolism is reduced compared with mouse and that RTV differentially affects human gene activity. These differences can affect responses to PIs in humanized mouse models of HIV-1 infection. Importantly, hCYP3A-NOG mice reconstituted with human immune cells can be used for bench-to-bedside translation.
抗逆转录病毒药物（ARV）的代谢主要与肝细胞色素 P450 活性有关。一类已知通过肠道和肝 CYP3A 代谢的 ARV 药物是蛋白酶抑制剂（PI）。CYP3A 抑制剂如考比司他和利托那韦（RTV）可提高血浆药物浓度。由于酶途径是人类特有的，因此此类药物相互作用的研究受到限制。虽然用人细胞重建的免疫缺陷小鼠是研究人类免疫缺陷病毒 1（HIV-1）感染期间 ARV 的极好模型，但它们不能反映人类的药物代谢。因此，我们创建了一种具有人妊娠相关蛋白 X 受体、组成型雄烷受体和 CYP3A4/7 基因的小鼠品系，这些基因位于 NOD.Cg- /JicTac 背景下（hCYP3A-NOG），并使用它们来评估人类 CYP3A 代谢对 ARV 药代动力学的影响。在概念验证研究中，我们使用了纳米制剂阿扎那韦（nanoATV）与或不与 RTV 一起使用。NOG 和 hCYP3A-NOG 小鼠每周接受 50mg/kg 纳米 ATV 单独治疗或用纳米制剂利托那韦（nanoATV/r）增强治疗。每周采集血浆，治疗后 28 天采集肝脏。纳米 ATV/r 治疗的 hCYP3A-NOG 小鼠血浆和肝中的纳米 ATV 浓度比复制的 NOG 小鼠高 2-4 倍。RTV 使 hCYP3A-NOG 小鼠和 NOG 小鼠的血浆和肝中 ATV 浓度分别增加 3 倍和 1.7 倍。结果表明，与小鼠相比，人类 CYP3A 介导的药物代谢减少，而 RTV 对人类基因活性的影响不同。这些差异可能会影响 HIV-1 感染的人源化小鼠模型中对 PI 的反应。重要的是，用人免疫细胞重建的 hCYP3A-NOG 小鼠可用于从实验室到临床的转化。
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