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

The Journal of Pharmacology and Experimental Therapeutics
JoEllyn M McMillanLarisa Y Poluektova

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 hCYP3...Continue Reading

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Citations

Aug 11, 2018·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Karl-Dimiter BissigXinxin Ding
Jul 4, 2019·Nature Communications·Prasanta K DashHoward E Gendelman
Jun 7, 2021·Retrovirology·Prasanta K DashHoward E Gendelman

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Methods Mentioned

BETA
transgenic
genotyping
PCR
PCRs
xenografts

Software Mentioned

GraphPad
GraphPad Prism

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