Cellular Pharmacokinetic Model-Based Analysis of Genistein, Glyceollin, and MK-571 Effects on 5 (and 6)-Carboxy-2′,7′-Dichloroflourescein Disposition in Caco-2 Cells

Callie Drennen, Erin Gorse, Robert Stratford Jr.

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Pharmacokinetic modeling was used to describe 5 (and 6)-carboxy-2′,7′-dichloroflourescein (CDF) disposition in Caco-2 cells following CDF or CDFDA (CDF diacetate) dosing. CDF transcellular flux was modeled by simple passive diffusion. CDFDA dosing models were based on simultaneous fitting of CDF levels in apical, basolateral, and intracellular compartments. Predicted CDF efflux was 50% higher across the apical versus the basolateral membrane. This difference was similar following apical and basolateral CDFDA dosing, despite intracellular levels being 3-fold higher following basolateral dosing, thus supporting nonsaturable CDF efflux kinetics. A 3-compartment catenary model with intracellular CDFDA hydrolysis described CDF disposition. This model predicted that apical CDF efflux was not altered in the presence of MK-571, and that basolateral membrane clearance was enhanced to account for reduced intracellular CDF in the presence of this multidrug resistance-associated protein (MRP) inhibitor. Similar effects were predicted for glyceollin, while genistein exposure had no predicted effects on CDF efflux. These modulator effects are discussed in the context of model predicted intracellular CDF concentrations relative to reports of CDF affinity (measured by Km) for MRP2 and MRP3. This model-based analysis confirms the complexity of efflux kinetics and suggests that other transporters may have contributed to CDF efflux.

Original languageEnglish (US)
Pages (from-to)1194-1203
Number of pages10
JournalJournal of Pharmaceutical Sciences
Volume107
Issue number4
DOIs
StatePublished - Apr 1 2018
Externally publishedYes

Fingerprint

verlukast
Caco-2 Cells
Genistein
Pharmacokinetics
Multidrug Resistance-Associated Proteins
Membranes
Systems Analysis
Hydrolysis
glyceollin

Keywords

  • active transport
  • Caco-2 cells
  • drug transport
  • efflux pumps
  • intestinal secretion/transport
  • membrane transport
  • pharmacokinetics
  • transcellular transport
  • transporters

ASJC Scopus subject areas

  • Pharmaceutical Science

Cite this

@article{d890a90899694b50bceef64e071e6c07,
title = "Cellular Pharmacokinetic Model-Based Analysis of Genistein, Glyceollin, and MK-571 Effects on 5 (and 6)-Carboxy-2′,7′-Dichloroflourescein Disposition in Caco-2 Cells",
abstract = "Pharmacokinetic modeling was used to describe 5 (and 6)-carboxy-2′,7′-dichloroflourescein (CDF) disposition in Caco-2 cells following CDF or CDFDA (CDF diacetate) dosing. CDF transcellular flux was modeled by simple passive diffusion. CDFDA dosing models were based on simultaneous fitting of CDF levels in apical, basolateral, and intracellular compartments. Predicted CDF efflux was 50{\%} higher across the apical versus the basolateral membrane. This difference was similar following apical and basolateral CDFDA dosing, despite intracellular levels being 3-fold higher following basolateral dosing, thus supporting nonsaturable CDF efflux kinetics. A 3-compartment catenary model with intracellular CDFDA hydrolysis described CDF disposition. This model predicted that apical CDF efflux was not altered in the presence of MK-571, and that basolateral membrane clearance was enhanced to account for reduced intracellular CDF in the presence of this multidrug resistance-associated protein (MRP) inhibitor. Similar effects were predicted for glyceollin, while genistein exposure had no predicted effects on CDF efflux. These modulator effects are discussed in the context of model predicted intracellular CDF concentrations relative to reports of CDF affinity (measured by Km) for MRP2 and MRP3. This model-based analysis confirms the complexity of efflux kinetics and suggests that other transporters may have contributed to CDF efflux.",
keywords = "active transport, Caco-2 cells, drug transport, efflux pumps, intestinal secretion/transport, membrane transport, pharmacokinetics, transcellular transport, transporters",
author = "Callie Drennen and Erin Gorse and {Stratford Jr.}, Robert",
year = "2018",
month = "4",
day = "1",
doi = "10.1016/j.xphs.2017.12.004",
language = "English (US)",
volume = "107",
pages = "1194--1203",
journal = "Journal of Pharmaceutical Sciences",
issn = "0022-3549",
publisher = "John Wiley and Sons Inc.",
number = "4",

}

TY - JOUR

T1 - Cellular Pharmacokinetic Model-Based Analysis of Genistein, Glyceollin, and MK-571 Effects on 5 (and 6)-Carboxy-2′,7′-Dichloroflourescein Disposition in Caco-2 Cells

AU - Drennen, Callie

AU - Gorse, Erin

AU - Stratford Jr., Robert

PY - 2018/4/1

Y1 - 2018/4/1

N2 - Pharmacokinetic modeling was used to describe 5 (and 6)-carboxy-2′,7′-dichloroflourescein (CDF) disposition in Caco-2 cells following CDF or CDFDA (CDF diacetate) dosing. CDF transcellular flux was modeled by simple passive diffusion. CDFDA dosing models were based on simultaneous fitting of CDF levels in apical, basolateral, and intracellular compartments. Predicted CDF efflux was 50% higher across the apical versus the basolateral membrane. This difference was similar following apical and basolateral CDFDA dosing, despite intracellular levels being 3-fold higher following basolateral dosing, thus supporting nonsaturable CDF efflux kinetics. A 3-compartment catenary model with intracellular CDFDA hydrolysis described CDF disposition. This model predicted that apical CDF efflux was not altered in the presence of MK-571, and that basolateral membrane clearance was enhanced to account for reduced intracellular CDF in the presence of this multidrug resistance-associated protein (MRP) inhibitor. Similar effects were predicted for glyceollin, while genistein exposure had no predicted effects on CDF efflux. These modulator effects are discussed in the context of model predicted intracellular CDF concentrations relative to reports of CDF affinity (measured by Km) for MRP2 and MRP3. This model-based analysis confirms the complexity of efflux kinetics and suggests that other transporters may have contributed to CDF efflux.

AB - Pharmacokinetic modeling was used to describe 5 (and 6)-carboxy-2′,7′-dichloroflourescein (CDF) disposition in Caco-2 cells following CDF or CDFDA (CDF diacetate) dosing. CDF transcellular flux was modeled by simple passive diffusion. CDFDA dosing models were based on simultaneous fitting of CDF levels in apical, basolateral, and intracellular compartments. Predicted CDF efflux was 50% higher across the apical versus the basolateral membrane. This difference was similar following apical and basolateral CDFDA dosing, despite intracellular levels being 3-fold higher following basolateral dosing, thus supporting nonsaturable CDF efflux kinetics. A 3-compartment catenary model with intracellular CDFDA hydrolysis described CDF disposition. This model predicted that apical CDF efflux was not altered in the presence of MK-571, and that basolateral membrane clearance was enhanced to account for reduced intracellular CDF in the presence of this multidrug resistance-associated protein (MRP) inhibitor. Similar effects were predicted for glyceollin, while genistein exposure had no predicted effects on CDF efflux. These modulator effects are discussed in the context of model predicted intracellular CDF concentrations relative to reports of CDF affinity (measured by Km) for MRP2 and MRP3. This model-based analysis confirms the complexity of efflux kinetics and suggests that other transporters may have contributed to CDF efflux.

KW - active transport

KW - Caco-2 cells

KW - drug transport

KW - efflux pumps

KW - intestinal secretion/transport

KW - membrane transport

KW - pharmacokinetics

KW - transcellular transport

KW - transporters

UR - http://www.scopus.com/inward/record.url?scp=85039923946&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85039923946&partnerID=8YFLogxK

U2 - 10.1016/j.xphs.2017.12.004

DO - 10.1016/j.xphs.2017.12.004

M3 - Article

VL - 107

SP - 1194

EP - 1203

JO - Journal of Pharmaceutical Sciences

JF - Journal of Pharmaceutical Sciences

SN - 0022-3549

IS - 4

ER -