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In vitro Pharmacokinetic Cell Culture System that Simulates Physiologic Drug and Nanoparticle Exposure to Macrophages

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Abstract

Purpose

An in vitro dynamic pharmacokinetic (PK) cell culture system was developed to more precisely simulate physiologic nanoparticle/drug exposure.

Methods

A dynamic PK cell culture system was developed to more closely reflect physiologic nanoparticle/drug concentrations that are changing with time. Macrophages were cultured in standard static and PK cell culture systems with rifampin (RIF; 5 μg/ml) or β-glucan, chitosan coated, poly(lactic-co-glycolic) acid (GLU-CS-PLGA) nanoparticles (RIF equivalent 5 μg/ml) for 6 h. Intracellular RIF concentrations were measured by UPLC/MS. Antimicrobial activity against M. smegmatis was tested in both PK and static systems.

Results

The dynamic PK cell culture system mimics a one-compartment elimination pharmacokinetic profile to properly mimic in vivo extracellular exposure. GLU-CS-PLGA nanoparticles increased intracellular RIF concentration by 37% compared to free drug in the dynamic cell culture system. GLU-CS-PLGA nanoparticles decreased M. smegmatis colony forming units compared to free drug in the dynamic cell culture system.

Conclusions

The PK cell culture system developed herein enables more precise simulation of human PK exposure (i.e., drug dosing and drug elimination curves) based on previously obtained PK parameters.

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Abbreviations

CFU :

Colony forming units

CS:

Chitosan

DAPI:

4′,6-diamidino-2-phenylindole

DCM:

Dichloromethane

DLS:

Dynamic light scattering

GLU:

1,3 β-glucan

HIV:

Human immunodeficiency virus

PK:

Pharmacokinetic

PLGA:

Poly(lactic-co-glycolic) acid

PVA:

Poly(vinyl alcohol)

RIF:

Rifampin

RifP:

Rifapentine

TB:

Tuberculosis

TEM:

Transmission electron microscope

UPLC-MS/MS :

Ultra performance liquid chromatography-tandem mass spectrometry

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Acknowledgments and Disclosures

Research reported in this publication was supported in part by 1R01AI129649-01A1 (NIAID) (JR); 1R56AI114298 (NIAID) (JR); University of Rochester Center for AIDS Research (CFAR) grant P30AI078498 (NIAID) (HK); and through a supplement to the University at Buffalo Pharmacology Specialty Laboratory, funded by UM1AI068634, UM1AI068636, and UM1AI106701 (NIAID)(GDM). HK was supported by Ruth L. Kirschstein National Research Service Award (NRSA) Institutional Research Training Grant 1T32GM099607 and UL1TR001412 (NCATS) (JR, HK). Research reported in this publication was supported in part by equipment donated by Waters Corporation. We acknowledge Dr. Martin Pavelka, University of Rochester, for the gernerous donation of M. Smegmatis. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

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Authors and Affiliations

  1. Translational Pharmacology Research Core, NYS Center of Excellence in Bioinformatics and Life Sciences, University at Buffalo, Buffalo, New York, 14203, USA

    Hilliard L. Kutscher & Gene D. Morse

  2. Institute for Lasers, Photonics and Biophotonics, University at Buffalo, Buffalo, New York, 14260, USA

    Hilliard L. Kutscher & Paras N. Prasad

  3. Department of Anesthesiology, University at Buffalo, Buffalo, New York, 14203, USA

    Hilliard L. Kutscher

  4. Department of Pharmacy Practice, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, New York, 14214, USA

    Gene D. Morse

  5. Department of Medicine, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, New York, 14203, USA

    Jessica L. Reynolds

Authors
  1. Hilliard L. Kutscher
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  2. Gene D. Morse
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  3. Paras N. Prasad
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  4. Jessica L. Reynolds
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Correspondence to Jessica L. Reynolds.

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Kutscher, H.L., Morse, G.D., Prasad, P.N. et al. In vitro Pharmacokinetic Cell Culture System that Simulates Physiologic Drug and Nanoparticle Exposure to Macrophages. Pharm Res 36, 44 (2019). https://doi.org/10.1007/s11095-019-2576-9

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  • DOI: https://doi.org/10.1007/s11095-019-2576-9

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