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Evaluation of Encequidar as An Intestinal P-gp and BCRP Specific Inhibitor to Assess the Role of Intestinal P-gp and BCRP in Drug-Drug Interactions

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Abstract

Purpose

The differences between intestinal and systemic (hepatic and renal) P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) roles in drug disposition are difficult to define. Accordingly, we characterized Encequidar (ECD) as an intestinal P-gp and BCRP specific inhibitor to evaluate their role in drug disposition.

Methods

We assessed the in vitro and in vivo inhibition potential of ECD towards human and animal P-gp and BCRP.

Results

ECD is a potent inhibitor with a high degree of selectivity in inhibiting human P-gp (hP-gp) over human BCRP (hBCRP) (IC50s of 0.0058 ± 0.0006 vs. > 10 µM, respectively). In contrast, ECD is a potent inhibitor of rat and cynomolgus monkey BCRP (IC50 ranged from 0.059 to 0.18 µM). While the AUC of IV paclitaxel (PTX) was significantly increased by elacridar (ELD) (P < 0.05) but not ECD in rats (15 mg/kg; PO) (2.55- vs. 0.93-fold), that of PO PTX was significantly elevated to a similar extent between the inhibitors (39.5- vs. 33.5-fold). Similarly, the AUC of PO sulfasalazine (SFZ) was dramatically increased by ELD and ECD (16.6- vs. 3.04-fold) although that of IV SFZ was not significantly affected by ELD and ECD in rats (1.18- vs. 1.06-fold). Finally, a comparable ECD-induced increase of the AUC of PO talinolol in cynomolgus monkeys was observed compared with ELD (2.14- vs. 2.12-fold).

Conclusions

ECD may allow an in-depth appraisal of the role of intestinal efflux transporter(s) in drug disposition in animals and humans through local intestinal drug interactions.

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Data availability

Upon request, and subject to review, Bristol Myers Squibb Company will provide the data that support the findings of this study.

Abbreviations

A-to-B:

Apical to basolateral direction

AMP:

Adenosine 5’-monophosphate

ATP:

Adenosine 5’-triphosphate

AUC :

Area under the plasma concentration–time curve

B-to-A:

Basolateral to apical direction

BCRP:

Breast cancer resistance protein

C max :

Total maximal concentration in plasma

C max,u :

Unbound maximal concentration in plasma

DDI:

Drug-drug interaction

HBSS:

Hanks’ balanced salt solution

ECD:

Encequidar

ELD:

Elacridar

ER:

Efflux ratio

FDA:

The United States Food and Drug Administration

IC 50 :

Half-maximal inhibitory concentration

I gut :

Maximum expected concentration in the intestinal lumen estimated as dose/250 mL

LC–MS/MS:

Liquid chromatography–tandem mass spectrometry

MDCK:

Madin-Darby canine kidney cell

MDR:

Multidrug resistance protein

MRP:

Multidrug resistance-associated protein

P-gp:

P-glycoprotein

PTX:

Paclitaxel

SFZ:

Sulfasalazine

SRM:

Selective reaction monitoring

TLN:

Talinolol

T max :

Time when peak plasma concentration occurs

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Acknowledgements

The authors thank Yueping Zhang (Bristol Myers Squibb Company) for help conducting some MDCK-hMDR1 and MDCK-hBCRP experiments.

Funding

This study was sponsored by Bristol Myers Squibb Company.

Author information

Author notes

  1. Jessica Chu and Erika Panfen Shared co-first authorship.

Authors and Affiliations

  1. Departments of Drug Metabolism and Pharmacokinetics, Bristol Myers Squibb Research and Development, Princeton, NJ, 08543, USA

    Jessica Chu, Erika Panfen, Anthony Marino, R. Marcus Fancher, Devang Shah, Michael Sinz & Hong Shen

  2. Nonclinical Disposition & Bioanalysis, Bristol Myers Squibb Research and Development, Princeton, NJ, 08543, USA

    Linna Wang & Yongjun Xue

  3. Discovery Pharmaceutics, Bristol Myers Squibb Research and Development, Princeton, NJ, 08543, USA

    Xue-Qing Chen

  4. Pharmaceutical Candidate Optimization, Biocon Bristol Myers Squibb R&D Centre (BBRC), Syngene International Ltd., Biocon Park, Bommasandra IV Phase, Bangalore, 560099, India

    Raviraj Landage, Omprakash Patil & Salil Dileep Desai

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Contributions

Design of work: Chu, Panfen, Fancher, Shah, Xue, Sinz, and Shen.

Conduction of experiments: Chu, Panfen, Wang, Marino, Chen, Landage, Patil, and Desai.

Analysis and interpretation of data: Chu, Panfen, Marino, Sinz, and Shen.

Drafting and revising work: Chu, Panfen, Landage, Sinz, and Shen.

Corresponding author

Correspondence to Hong Shen.

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Conflict of Interest

All authors are employees of either Bristol Myers Squibb Company or Biocon Bristol Myers Squibb R&D Centre, Syngene International Ltd.

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Chu, J., Panfen, E., Wang, L. et al. Evaluation of Encequidar as An Intestinal P-gp and BCRP Specific Inhibitor to Assess the Role of Intestinal P-gp and BCRP in Drug-Drug Interactions. Pharm Res 40, 2567–2584 (2023). https://doi.org/10.1007/s11095-023-03563-4

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