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J Pharmacol Exp Ther. 2018 May;365(2):272-280. doi: 10.1124/jpet.117.247288. Epub 2018 Feb 23.

Antiretroviral Drug Metabolism in Humanized PXR-CAR-CYP3A-NOG Mice.

Author information

1
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 lpoluekt@unmc.edu cgurumurthy@unmc.edu jmmcmillan@unmc.edu.
2
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.

Abstract

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-Prkdcscid Il2rgtm1Sug /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.

PMID:
29476044
PMCID:
PMC5878674
DOI:
10.1124/jpet.117.247288
[Indexed for MEDLINE]
Free PMC Article

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