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Assessing Trans-Inhibition of OATP1B1 and OATP1B3 by Calcineurin and/or PPIase Inhibitors and Global Identification of OATP1B1/3-Associated Proteins

Publication ,  Journal Article
Powell, JT; Kayesh, R; Ballesteros-Perez, A; Alam, K; Niyonshuti, P; Soderblom, EJ; Ding, K; Xu, C; Yue, W
Published in: Pharmaceutics
January 1, 2024

Organic anion transporting polypeptide (OATP) 1B1 and OATP1B3 are key determinants of drug–drug interactions (DDIs). Various drugs including the calcineurin inhibitor (CNI) cyclosporine A (CsA) exert preincubation-induced trans-inhibitory effects upon OATP1B1 and/or OATP1B3 (abbreviated as OATP1B1/3) by unknown mechanism(s). OATP1B1/3 are phosphoproteins; calcineurin, which dephosphorylates and regulates numerous phosphoproteins, has not previously been investigated in the context of preincubation-induced trans-inhibition of OATP1B1/3. Herein, we compare the trans-inhibitory effects exerted on OATP1B1 and OATP1B3 by CsA, the non-analogous CNI tacrolimus, and the non-CNI CsA analogue SCY-635 in transporter-overexpressing human embryonic kidney (HEK) 293 stable cell lines. Preincubation (10–60 min) with tacrolimus (1–10 µM) rapidly and significantly reduces OATP1B1- and OATP1B3-mediated transport up to 0.18 ± 0.03- and 0.20 ± 0.02-fold compared to the control, respectively. Both CsA and SCY-635 can trans-inhibit OATP1B1, with the inhibitory effects progressively increasing over a 60 min preincubation time. At each equivalent preincubation time, CsA has greater trans-inhibitory effects toward OATP1B1 than SCY-635. Preincubation with SCY-635 for 60 min yielded IC50 of 2.2 ± 1.4 µM against OATP1B1, which is ~18 fold greater than that of CsA (0.12 ± 0.04 µM). Furthermore, a proteomics-based screening for protein interactors was used to examine possible proteins and processes contributing to OATP1B1/3 regulation and preincubation-induced inhibition by CNIs and other drugs. A total of 861 and 357 proteins were identified as specifically associated with OATP1B1 and OATP1B3, respectively, including various protein kinases, ubiquitin-related enzymes, the tacrolimus (FK506)-binding proteins FKBP5 and FKBP8, and several known regulatory targets of calcineurin. The current study reports several novel findings that expand our understanding of impaired OATP1B1/3 function; these include preincubation-induced trans-inhibition of OATP1B1/3 by the CNI tacrolimus, greater preincubation-induced inhibition by CsA compared to its non-CNI analogue SCY-635, and association of OATP1B1/3 with various proteins relevant to established and candidate OATP1B1/3 regulatory processes.

Duke Scholars

Published In

Pharmaceutics

DOI

EISSN

1999-4923

Publication Date

January 1, 2024

Volume

16

Issue

1

Related Subject Headings

  • 3214 Pharmacology and pharmaceutical sciences
  • 1115 Pharmacology and Pharmaceutical Sciences
 

Citation

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Powell, J. T., Kayesh, R., Ballesteros-Perez, A., Alam, K., Niyonshuti, P., Soderblom, E. J., … Yue, W. (2024). Assessing Trans-Inhibition of OATP1B1 and OATP1B3 by Calcineurin and/or PPIase Inhibitors and Global Identification of OATP1B1/3-Associated Proteins. Pharmaceutics, 16(1). https://doi.org/10.3390/pharmaceutics16010063
Powell, J. T., R. Kayesh, A. Ballesteros-Perez, K. Alam, P. Niyonshuti, E. J. Soderblom, K. Ding, C. Xu, and W. Yue. “Assessing Trans-Inhibition of OATP1B1 and OATP1B3 by Calcineurin and/or PPIase Inhibitors and Global Identification of OATP1B1/3-Associated Proteins.” Pharmaceutics 16, no. 1 (January 1, 2024). https://doi.org/10.3390/pharmaceutics16010063.
Powell JT, Kayesh R, Ballesteros-Perez A, Alam K, Niyonshuti P, Soderblom EJ, et al. Assessing Trans-Inhibition of OATP1B1 and OATP1B3 by Calcineurin and/or PPIase Inhibitors and Global Identification of OATP1B1/3-Associated Proteins. Pharmaceutics. 2024 Jan 1;16(1).
Powell, J. T., et al. “Assessing Trans-Inhibition of OATP1B1 and OATP1B3 by Calcineurin and/or PPIase Inhibitors and Global Identification of OATP1B1/3-Associated Proteins.” Pharmaceutics, vol. 16, no. 1, Jan. 2024. Scopus, doi:10.3390/pharmaceutics16010063.
Powell JT, Kayesh R, Ballesteros-Perez A, Alam K, Niyonshuti P, Soderblom EJ, Ding K, Xu C, Yue W. Assessing Trans-Inhibition of OATP1B1 and OATP1B3 by Calcineurin and/or PPIase Inhibitors and Global Identification of OATP1B1/3-Associated Proteins. Pharmaceutics. 2024 Jan 1;16(1).

Published In

Pharmaceutics

DOI

EISSN

1999-4923

Publication Date

January 1, 2024

Volume

16

Issue

1

Related Subject Headings

  • 3214 Pharmacology and pharmaceutical sciences
  • 1115 Pharmacology and Pharmaceutical Sciences