Interplay of OATP1A/1B/2B1 uptake transporters and ABCB1 and ABCG2 efflux transporters in the handling of bilirubin and drugs

Wenlong Li; Rolf W Sparidans; Yaogeng Wang; Margarida L F Martins; Dirk R de Waart; Olaf van Tellingen; Ji-Ying Song; Maria C Lebre; Stéphanie van Hoppe; Els Wagenaar; Jos H Beijnen; Alfred H Schinkel

doi:10.1016/j.biopha.2024.116644

Interplay of OATP1A/1B/2B1 uptake transporters and ABCB1 and ABCG2 efflux transporters in the handling of bilirubin and drugs

Wenlong Li^*
, Rolf W Sparidans
, Yaogeng Wang
, Margarida L F Martins
, Dirk R de Waart
, Olaf van Tellingen
, Ji-Ying Song
, Maria C Lebre
, Stéphanie van Hoppe
, Els Wagenaar
, Jos H Beijnen
, Alfred H Schinkel

^*Corresponding author for this work

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

Abstract

Transmembrane drug transporters can be important determinants of the pharmacokinetics, efficacy, and safety profiles of drugs. To investigate the potential cooperative and/or counteracting interplay of OATP1A/1B/2B1 uptake transporters and ABCB1 and ABCG2 efflux transporters in physiology and pharmacology, we generated a new mouse model (Bab12), deficient for Slco1a/1b, Slco2b1, Abcb1a/1b and Abcg2. Bab12 mice were viable and fertile. We compared wild-type, Slco1a/1b/2b1^-/-, Abcb1a/1b;Abcg2^-/- and Bab12 strains. Endogenous plasma conjugated bilirubin levels ranked as follows: wild-type = Abcb1a/1b;Abcg2^-/- << Slco1a/1b/2b1^-/- < Bab12 mice. Plasma levels of rosuvastatin and fexofenadine were elevated in Slco1a/1b/2b1^-/- and Abcb1a/1b;Abcg2^-/- mice compared to wild-type, and dramatically increased in Bab12 mice. Although systemic exposure of larotrectinib and repotrectinib was substantially increased in the separate multidrug transporter knockout strains, no additive effects were observed in the combination Bab12 mice. Significantly higher plasma exposure of fluvastatin and pravastatin was only found in Slco1a/1b/2b1-deficient mice. However, noticeable transport by Slco1a/1b/2b1 and Abcb1a/1b and Abcg2 across the BBB was observed for fluvastatin and pravastatin, respectively, by comparing Bab12 mice with Abcb1a/1b;Abcg2^-/- or Slco1a/1b/2b1^-/- mice. Quite varying behavior in plasma exposure of erlotinib and its metabolites was observed among these strains. Bab12 mice revealed that Abcb1a/1b and/or Abcg2 can contribute to conjugated bilirubin elimination when Slco1a/1b/2b1 are absent. Our results suggest that the interplay of Slco1a/1b/2b1, Abcb1a/1b, and Abcg2 could markedly affect the pharmacokinetics of some, but not all drugs and metabolites. The Bab12 mouse model will represent a useful tool for optimizing drug development and clinical application, including efficacy and safety.

Original language	English
Article number	116644
Number of pages	17
Journal	Biomedicine and Pharmacotherapy
Volume	175
Early online date	30 Apr 2024
DOIs	https://doi.org/10.1016/j.biopha.2024.116644
Publication status	Published - Jun 2024

Bibliographical note

Publisher Copyright:
© 2024 The Authors

Funding

We gratefully acknowledge the support from the Genomic Core Facility of the Netherlands Cancer Institute in performing RNA sequencing analysis. We also thank Bart van Wijnen of the Clinical Chemistry lab at the Netherlands Cancer Institute for the clinical chemistry measurements of mouse plasma. We are further grateful for the support from the animal facility of the Netherlands Cancer Institute.

Funders
Netherlands Cancer Institute

Keywords

Bilirubin
Interplay
Novel mouse model
Plasma exposure
Tissue distribution
Transmembrane drug transporters

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1-s2.0-S0753332224005286-mainFinal published version, 11.7 MBLicence: CC BY

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Li, W., Sparidans, R. W., Wang, Y., Martins, M. L. F., de Waart, D. R., van Tellingen, O., Song, J.-Y., Lebre, M. C., van Hoppe, S., Wagenaar, E., Beijnen, J. H., & Schinkel, A. H. (2024). Interplay of OATP1A/1B/2B1 uptake transporters and ABCB1 and ABCG2 efflux transporters in the handling of bilirubin and drugs. Biomedicine and Pharmacotherapy, 175, Article 116644. https://doi.org/10.1016/j.biopha.2024.116644

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title = "Interplay of OATP1A/1B/2B1 uptake transporters and ABCB1 and ABCG2 efflux transporters in the handling of bilirubin and drugs",

abstract = "Transmembrane drug transporters can be important determinants of the pharmacokinetics, efficacy, and safety profiles of drugs. To investigate the potential cooperative and/or counteracting interplay of OATP1A/1B/2B1 uptake transporters and ABCB1 and ABCG2 efflux transporters in physiology and pharmacology, we generated a new mouse model (Bab12), deficient for Slco1a/1b, Slco2b1, Abcb1a/1b and Abcg2. Bab12 mice were viable and fertile. We compared wild-type, Slco1a/1b/2b1-/-, Abcb1a/1b;Abcg2-/- and Bab12 strains. Endogenous plasma conjugated bilirubin levels ranked as follows: wild-type = Abcb1a/1b;Abcg2-/- << Slco1a/1b/2b1-/- < Bab12 mice. Plasma levels of rosuvastatin and fexofenadine were elevated in Slco1a/1b/2b1-/- and Abcb1a/1b;Abcg2-/- mice compared to wild-type, and dramatically increased in Bab12 mice. Although systemic exposure of larotrectinib and repotrectinib was substantially increased in the separate multidrug transporter knockout strains, no additive effects were observed in the combination Bab12 mice. Significantly higher plasma exposure of fluvastatin and pravastatin was only found in Slco1a/1b/2b1-deficient mice. However, noticeable transport by Slco1a/1b/2b1 and Abcb1a/1b and Abcg2 across the BBB was observed for fluvastatin and pravastatin, respectively, by comparing Bab12 mice with Abcb1a/1b;Abcg2-/- or Slco1a/1b/2b1-/- mice. Quite varying behavior in plasma exposure of erlotinib and its metabolites was observed among these strains. Bab12 mice revealed that Abcb1a/1b and/or Abcg2 can contribute to conjugated bilirubin elimination when Slco1a/1b/2b1 are absent. Our results suggest that the interplay of Slco1a/1b/2b1, Abcb1a/1b, and Abcg2 could markedly affect the pharmacokinetics of some, but not all drugs and metabolites. The Bab12 mouse model will represent a useful tool for optimizing drug development and clinical application, including efficacy and safety.",

keywords = "Bilirubin, Interplay, Novel mouse model, Plasma exposure, Tissue distribution, Transmembrane drug transporters",

author = "Wenlong Li and Sparidans, \{Rolf W\} and Yaogeng Wang and Martins, \{Margarida L F\} and \{de Waart\}, \{Dirk R\} and \{van Tellingen\}, Olaf and Ji-Ying Song and Lebre, \{Maria C\} and \{van Hoppe\}, St{\'e}phanie and Els Wagenaar and Beijnen, \{Jos H\} and Schinkel, \{Alfred H\}",

note = "Publisher Copyright: {\textcopyright} 2024 The Authors",

year = "2024",

month = jun,

doi = "10.1016/j.biopha.2024.116644",

language = "English",

volume = "175",

journal = "Biomedicine and Pharmacotherapy",

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Li, W, Sparidans, RW, Wang, Y, Martins, MLF, de Waart, DR, van Tellingen, O, Song, J-Y, Lebre, MC, van Hoppe, S, Wagenaar, E, Beijnen, JH & Schinkel, AH 2024, 'Interplay of OATP1A/1B/2B1 uptake transporters and ABCB1 and ABCG2 efflux transporters in the handling of bilirubin and drugs', Biomedicine and Pharmacotherapy, vol. 175, 116644. https://doi.org/10.1016/j.biopha.2024.116644

TY - JOUR

T1 - Interplay of OATP1A/1B/2B1 uptake transporters and ABCB1 and ABCG2 efflux transporters in the handling of bilirubin and drugs

AU - Li, Wenlong

AU - Sparidans, Rolf W

AU - Wang, Yaogeng

AU - Martins, Margarida L F

AU - de Waart, Dirk R

AU - van Tellingen, Olaf

AU - Song, Ji-Ying

AU - Lebre, Maria C

AU - van Hoppe, Stéphanie

AU - Wagenaar, Els

AU - Beijnen, Jos H

AU - Schinkel, Alfred H

PY - 2024/6

Y1 - 2024/6

N2 - Transmembrane drug transporters can be important determinants of the pharmacokinetics, efficacy, and safety profiles of drugs. To investigate the potential cooperative and/or counteracting interplay of OATP1A/1B/2B1 uptake transporters and ABCB1 and ABCG2 efflux transporters in physiology and pharmacology, we generated a new mouse model (Bab12), deficient for Slco1a/1b, Slco2b1, Abcb1a/1b and Abcg2. Bab12 mice were viable and fertile. We compared wild-type, Slco1a/1b/2b1-/-, Abcb1a/1b;Abcg2-/- and Bab12 strains. Endogenous plasma conjugated bilirubin levels ranked as follows: wild-type = Abcb1a/1b;Abcg2-/- << Slco1a/1b/2b1-/- < Bab12 mice. Plasma levels of rosuvastatin and fexofenadine were elevated in Slco1a/1b/2b1-/- and Abcb1a/1b;Abcg2-/- mice compared to wild-type, and dramatically increased in Bab12 mice. Although systemic exposure of larotrectinib and repotrectinib was substantially increased in the separate multidrug transporter knockout strains, no additive effects were observed in the combination Bab12 mice. Significantly higher plasma exposure of fluvastatin and pravastatin was only found in Slco1a/1b/2b1-deficient mice. However, noticeable transport by Slco1a/1b/2b1 and Abcb1a/1b and Abcg2 across the BBB was observed for fluvastatin and pravastatin, respectively, by comparing Bab12 mice with Abcb1a/1b;Abcg2-/- or Slco1a/1b/2b1-/- mice. Quite varying behavior in plasma exposure of erlotinib and its metabolites was observed among these strains. Bab12 mice revealed that Abcb1a/1b and/or Abcg2 can contribute to conjugated bilirubin elimination when Slco1a/1b/2b1 are absent. Our results suggest that the interplay of Slco1a/1b/2b1, Abcb1a/1b, and Abcg2 could markedly affect the pharmacokinetics of some, but not all drugs and metabolites. The Bab12 mouse model will represent a useful tool for optimizing drug development and clinical application, including efficacy and safety.

AB - Transmembrane drug transporters can be important determinants of the pharmacokinetics, efficacy, and safety profiles of drugs. To investigate the potential cooperative and/or counteracting interplay of OATP1A/1B/2B1 uptake transporters and ABCB1 and ABCG2 efflux transporters in physiology and pharmacology, we generated a new mouse model (Bab12), deficient for Slco1a/1b, Slco2b1, Abcb1a/1b and Abcg2. Bab12 mice were viable and fertile. We compared wild-type, Slco1a/1b/2b1-/-, Abcb1a/1b;Abcg2-/- and Bab12 strains. Endogenous plasma conjugated bilirubin levels ranked as follows: wild-type = Abcb1a/1b;Abcg2-/- << Slco1a/1b/2b1-/- < Bab12 mice. Plasma levels of rosuvastatin and fexofenadine were elevated in Slco1a/1b/2b1-/- and Abcb1a/1b;Abcg2-/- mice compared to wild-type, and dramatically increased in Bab12 mice. Although systemic exposure of larotrectinib and repotrectinib was substantially increased in the separate multidrug transporter knockout strains, no additive effects were observed in the combination Bab12 mice. Significantly higher plasma exposure of fluvastatin and pravastatin was only found in Slco1a/1b/2b1-deficient mice. However, noticeable transport by Slco1a/1b/2b1 and Abcb1a/1b and Abcg2 across the BBB was observed for fluvastatin and pravastatin, respectively, by comparing Bab12 mice with Abcb1a/1b;Abcg2-/- or Slco1a/1b/2b1-/- mice. Quite varying behavior in plasma exposure of erlotinib and its metabolites was observed among these strains. Bab12 mice revealed that Abcb1a/1b and/or Abcg2 can contribute to conjugated bilirubin elimination when Slco1a/1b/2b1 are absent. Our results suggest that the interplay of Slco1a/1b/2b1, Abcb1a/1b, and Abcg2 could markedly affect the pharmacokinetics of some, but not all drugs and metabolites. The Bab12 mouse model will represent a useful tool for optimizing drug development and clinical application, including efficacy and safety.

KW - Bilirubin

KW - Interplay

KW - Novel mouse model

KW - Plasma exposure

KW - Tissue distribution

KW - Transmembrane drug transporters

UR - https://www.scopus.com/pages/publications/85191476791

U2 - 10.1016/j.biopha.2024.116644

DO - 10.1016/j.biopha.2024.116644

M3 - Article

C2 - 38692057

SN - 0753-3322

VL - 175

JO - Biomedicine and Pharmacotherapy

JF - Biomedicine and Pharmacotherapy

M1 - 116644

ER -

Interplay of OATP1A/1B/2B1 uptake transporters and ABCB1 and ABCG2 efflux transporters in the handling of bilirubin and drugs

Abstract

Bibliographical note

Funding

Keywords

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