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pH Dependent but not P-gp Dependent Bidirectional Transport Study of S-propranolol: The Importance of Passive Diffusion

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Abstract

Purpose

Recent controversial publications, citing studies purporting to show that P-gp mediates the transport of propranolol, proposed that passive biological membrane transport is negligible. Based on the BDDCS, the extensively metabolized-highly permeable-highly soluble BDDCS class 1 drug, propranolol, shows a high passive permeability at concentrations unrestricted by solubility that can overwhelm any potential transporter effects. Here we reinvestigate the effects of passive diffusion and carrier-mediated transport on S-propranolol.

Methods

Bidirectional permeability and inhibition of efflux transport studies were carried out in MDCK, MDCK-MDR1 and Caco-2 cell lines at different concentrations. Transcellular permeability studies were conducted at different apical pHs in the rat jejunum Ussing chamber model and PAMPA system.

Results

S-propranolol exhibited efflux ratios lower than 1 in MDCK, MDCK-MDR1 and Caco-2 cells. No significant differences of Papp, B->A in the presence and absence of the efflux inhibitor GG918 were observed. However, an efflux ratio of 3.63 was found at apical pH 6.5 with significant decrease in Papp, A->B and increase in Papp, B->A compared to apical pH 7.4 in Caco-2 cell lines. The pH dependent permeability was confirmed in the Ussing chamber model. S-propranolol flux was unchanged during inhibition by verapamil and rifampin. Furthermore, pH dependent permeability was also observed in the PAMPA system.

Conclusions

S-propranolol does not exhibit active transport as proposed previously. The “false” positive efflux ratio can be explained by the pH partition theory. As expected, passive diffusion, but not active transport, plays the primary role in the permeability of the BDDCS class 1 drug propranolol.

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Abbreviations

ASBT:

Apical sodium/bile acid co-transporter

BCRP:

Breast cancer resistance protein

BDDCS:

Biopharmaceutics drug disposition classification system

FBS:

Fetal bovine serum

GG918(GF120918):

N-{4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)-ethyl]-phenyl}-9,10-dihydro-5-methoxy-9-oxo-4-acridinecarboxamide

HBSS:

Hank’s balanced salt solution

MCT:

Monocarboxylic acid transporter

MDCK:

Madin-Darby canine kidney

MRP:

multidrug resistance like protein

OATP:

Organic anion transporting polypeptide

OCT:

Organic cation transporter

PAMPA:

Parallel artificial membrane permeability assay

Papp :

Apparent permeability coefficient

Papp A->B :

Apical-to-basolateral Papp

Papp B->A :

Basolateral-to-apical Papp

PEPT:

Proton-coupled oligopeptide transporter

P-gp (MDR1):

P-glycoprotein

TEER:

Transepithelial electrical resistance

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ACKNOWLEDGMENTS AND DISCLOSURES

We thank the Chinese Scholarship Council for providing financial support for Yi Zheng to study and carry out these studies in Dr. Benet’s laboratory at the University of California, San Francisco. The studies in Dr. Benet’s lab were funded in part by NIH grants RR031474 and GM061390.

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Authors and Affiliations

  1. Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, #24 Tongjiaxiang, Mailbox 210, Nanjing, 210009, Jiangsu, China

    Yi Zheng & Xijing Chen

  2. Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, 533 Parnassus Avenue, San Francisco, California, 94143-0912, USA

    Yi Zheng, Leslie Z. Benet & Hideaki Okochi

Authors
  1. Yi Zheng
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  2. Leslie Z. Benet
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  3. Hideaki Okochi
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  4. Xijing Chen
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Correspondence to Xijing Chen.

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Zheng, Y., Benet, L.Z., Okochi, H. et al. pH Dependent but not P-gp Dependent Bidirectional Transport Study of S-propranolol: The Importance of Passive Diffusion. Pharm Res 32, 2516–2526 (2015). https://doi.org/10.1007/s11095-015-1640-3

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  • DOI: https://doi.org/10.1007/s11095-015-1640-3

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