Investigation of the micellar effect of pluronic P85 on P-glycoprotein inhibition: Cell accumulation and equilibrium dialysis studies

Shaik Naveed; Giri Nagdeep; William F. Elmquist

doi:10.1002/jps.21723

Investigation of the micellar effect of pluronic P85 on P-glycoprotein inhibition: Cell accumulation and equilibrium dialysis studies

Shaik Naveed, Giri Nagdeep, William F. Elmquist

Research output: Contribution to journal › Article › peer-review

28 Scopus citations

Abstract

The objective of this study was: (1) to characterize the P-gp inhibitory effect of different concentrations of Pluronic P85 on anti-HIV-1 drug cellular accumulation, and (2) to investigate the relationship between cellular accumulation and free fraction of drug. Cellular accumulation studies in MDCKII-WT and MDCKII-MDR1 cell monolayers showed a biphasic dose response characterized by decline in accumulation at Pluronic concentrations greater than the CMC. This phenomenon was independent of the inhibition of P-gp efflux by Pluronic. Cell-free equilibrium dialysis was used to determine the effect of Pluronic P85 on drug free fraction and the affinity of Pluronic micelles for drug was modeled. Nelfinavir and saquinavir associated extensively with micelles and equilibrium free fractions were low at P85 concentrations above the CMC, with association constants being in the order nelfinavir > saquinavir ⋙ abacavir. abacavir. Abacavir, a P-gp substrate, showed no association with micelles yet showed a biphasic response in cellular accumulation. These data suggest that, above the CMC, inhibition of P-gp is not affected but rather factors such as micellar trapping could contribute to decreased accumulation. Therefore, the in vitro evaluation of the effect of Pluronic formulations on active transport should take into account both the physicochemical properties of drug and the composition of Pluronic.

Original language	English (US)
Pages (from-to)	4170-4190
Number of pages	21
Journal	Journal of Pharmaceutical Sciences
Volume	98
Issue number	11
DOIs	https://doi.org/10.1002/jps.21723
State	Published - Nov 2009

Bibliographical note

Funding Information:
This work was supported by National Institutes of Health Grant NS42549. We thank Dr. Piet Borst from the Netherlands Cancer Institute for generously providing the parent MDCKII and P-gp over-expressing MDCKII cells. We would like to thank BASF for generously providing us with Pluronics and to GlaxoSmithKline for their gift of GF120198.

Keywords

Critical micellar concentration
Efflux pumps
Equilibrium dialysis
HIV-1 protease inhibitors
Micelle
P-glycoprotein
Pluronics
Polymers

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1002/jps.21723

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title = "Investigation of the micellar effect of pluronic P85 on P-glycoprotein inhibition: Cell accumulation and equilibrium dialysis studies",

abstract = "The objective of this study was: (1) to characterize the P-gp inhibitory effect of different concentrations of Pluronic P85 on anti-HIV-1 drug cellular accumulation, and (2) to investigate the relationship between cellular accumulation and free fraction of drug. Cellular accumulation studies in MDCKII-WT and MDCKII-MDR1 cell monolayers showed a biphasic dose response characterized by decline in accumulation at Pluronic concentrations greater than the CMC. This phenomenon was independent of the inhibition of P-gp efflux by Pluronic. Cell-free equilibrium dialysis was used to determine the effect of Pluronic P85 on drug free fraction and the affinity of Pluronic micelles for drug was modeled. Nelfinavir and saquinavir associated extensively with micelles and equilibrium free fractions were low at P85 concentrations above the CMC, with association constants being in the order nelfinavir > saquinavir ⋙ abacavir. abacavir. Abacavir, a P-gp substrate, showed no association with micelles yet showed a biphasic response in cellular accumulation. These data suggest that, above the CMC, inhibition of P-gp is not affected but rather factors such as micellar trapping could contribute to decreased accumulation. Therefore, the in vitro evaluation of the effect of Pluronic formulations on active transport should take into account both the physicochemical properties of drug and the composition of Pluronic.",

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author = "Shaik Naveed and Giri Nagdeep and Elmquist, {William F.}",

note = "Funding Information: This work was supported by National Institutes of Health Grant NS42549. We thank Dr. Piet Borst from the Netherlands Cancer Institute for generously providing the parent MDCKII and P-gp over-expressing MDCKII cells. We would like to thank BASF for generously providing us with Pluronics and to GlaxoSmithKline for their gift of GF120198.",

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AU - Naveed, Shaik

AU - Nagdeep, Giri

AU - Elmquist, William F.

N1 - Funding Information: This work was supported by National Institutes of Health Grant NS42549. We thank Dr. Piet Borst from the Netherlands Cancer Institute for generously providing the parent MDCKII and P-gp over-expressing MDCKII cells. We would like to thank BASF for generously providing us with Pluronics and to GlaxoSmithKline for their gift of GF120198.

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N2 - The objective of this study was: (1) to characterize the P-gp inhibitory effect of different concentrations of Pluronic P85 on anti-HIV-1 drug cellular accumulation, and (2) to investigate the relationship between cellular accumulation and free fraction of drug. Cellular accumulation studies in MDCKII-WT and MDCKII-MDR1 cell monolayers showed a biphasic dose response characterized by decline in accumulation at Pluronic concentrations greater than the CMC. This phenomenon was independent of the inhibition of P-gp efflux by Pluronic. Cell-free equilibrium dialysis was used to determine the effect of Pluronic P85 on drug free fraction and the affinity of Pluronic micelles for drug was modeled. Nelfinavir and saquinavir associated extensively with micelles and equilibrium free fractions were low at P85 concentrations above the CMC, with association constants being in the order nelfinavir > saquinavir ⋙ abacavir. abacavir. Abacavir, a P-gp substrate, showed no association with micelles yet showed a biphasic response in cellular accumulation. These data suggest that, above the CMC, inhibition of P-gp is not affected but rather factors such as micellar trapping could contribute to decreased accumulation. Therefore, the in vitro evaluation of the effect of Pluronic formulations on active transport should take into account both the physicochemical properties of drug and the composition of Pluronic.

AB - The objective of this study was: (1) to characterize the P-gp inhibitory effect of different concentrations of Pluronic P85 on anti-HIV-1 drug cellular accumulation, and (2) to investigate the relationship between cellular accumulation and free fraction of drug. Cellular accumulation studies in MDCKII-WT and MDCKII-MDR1 cell monolayers showed a biphasic dose response characterized by decline in accumulation at Pluronic concentrations greater than the CMC. This phenomenon was independent of the inhibition of P-gp efflux by Pluronic. Cell-free equilibrium dialysis was used to determine the effect of Pluronic P85 on drug free fraction and the affinity of Pluronic micelles for drug was modeled. Nelfinavir and saquinavir associated extensively with micelles and equilibrium free fractions were low at P85 concentrations above the CMC, with association constants being in the order nelfinavir > saquinavir ⋙ abacavir. abacavir. Abacavir, a P-gp substrate, showed no association with micelles yet showed a biphasic response in cellular accumulation. These data suggest that, above the CMC, inhibition of P-gp is not affected but rather factors such as micellar trapping could contribute to decreased accumulation. Therefore, the in vitro evaluation of the effect of Pluronic formulations on active transport should take into account both the physicochemical properties of drug and the composition of Pluronic.

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JF - Journal of Pharmaceutical Sciences

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ER -

Investigation of the micellar effect of pluronic P85 on P-glycoprotein inhibition: Cell accumulation and equilibrium dialysis studies

Abstract

Bibliographical note

Keywords

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