RT Journal Article
SR Electronic
T1 Antiretroviral Drug Metabolism in Humanized PXR-CAR-CYP3A-NOG Mice
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 272
OP 280
DO 10.1124/jpet.117.247288
VO 365
IS 2
A1 JoEllyn M. McMillan
A1 Denise A. Cobb
A1 Zhiyi Lin
A1 Mary G. Banoub
A1 Raghubendra S. Dagur
A1 Amanda A. Branch Woods
A1 Weimin Wang
A1 Edward Makarov
A1 Ted Kocher
A1 Poonam S. Joshi
A1 Rolen M. Quadros
A1 Donald W. Harms
A1 Samuel M. Cohen
A1 Howard E. Gendelman
A1 Channabasavaiah B. Gurumurthy
A1 Santhi Gorantla
A1 Larisa Y. Poluektova
YR 2018
UL http://jpet.aspetjournals.org/content/365/2/272.abstract
AB 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.