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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.

Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Wenlong Li reports financial support was provided by China Scholarship Council and National Natural Science Foundation of China. Yaogeng Wang reports financial support was provided by China Scholarship Council. Margarida Martins reports financial support was provided by DiacetylM BV. Alfred Schinkel reports a relationship with Taconic Biosciences Inc that includes: funding grants.

Titel:	Interplay of OATP1A/1B/2B1 uptake transporters and ABCB1 and ABCG2 efflux transporters in the handling of bilirubin and drugs.
Autor/in / Beteiligte Person:	Li, W ; Sparidans, RW ; Wang, Y ; Martins, MLF ; de Waart DR ; van Tellingen O ; Song, JY ; Lebre, MC ; van Hoppe S ; Wagenaar, E ; Beijnen, JH ; Schinkel, AH
Link:	Full Text Finder (Volltext)
Zeitschrift:	Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, Jg. 175 (2024-06-01), S. 116644
Veröffentlichung:	Paris : Editions Scientifiques Elsevier ; <i>Original Publication</i>: New York, N.Y. : Masson Pub. USA, Inc., c1982-, 2024
Medientyp:	academicJournal
ISSN:	1950-6007 (electronic)
DOI:	10.1016/j.biopha.2024.116644
Schlagwort:	Animals Mice Liver-Specific Organic Anion Transporter 1 metabolism Liver-Specific Organic Anion Transporter 1 genetics Terfenadine pharmacokinetics Terfenadine analogs & derivatives Male Biological Transport Rosuvastatin Calcium pharmacokinetics Rosuvastatin Calcium pharmacology Mice, Inbred C57BL ATP Binding Cassette Transporter, Subfamily G, Member 2 metabolism ATP Binding Cassette Transporter, Subfamily G, Member 2 genetics Bilirubin blood Bilirubin metabolism ATP Binding Cassette Transporter, Subfamily B genetics ATP Binding Cassette Transporter, Subfamily B metabolism Mice, Knockout Organic Anion Transporters metabolism Organic Anion Transporters genetics
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Publication Type: Journal Article Language: English [Biomed Pharmacother] 2024 Jun; Vol. 175, pp. 116644. <i>Date of Electronic Publication: </i>2024 Apr 30. MeSH Terms: ATP Binding Cassette Transporter, Subfamily G, Member 2* / metabolism ; ATP Binding Cassette Transporter, Subfamily G, Member 2* / genetics ; Bilirubin* / blood ; Bilirubin* / metabolism ; ATP Binding Cassette Transporter, Subfamily B* / genetics ; ATP Binding Cassette Transporter, Subfamily B* / metabolism ; Mice, Knockout* ; Organic Anion Transporters* / metabolism ; Organic Anion Transporters* / genetics ; Animals ; Mice ; Liver-Specific Organic Anion Transporter 1 / metabolism ; Liver-Specific Organic Anion Transporter 1 / genetics ; Terfenadine / pharmacokinetics ; Terfenadine / analogs & derivatives ; Male ; Biological Transport ; Rosuvastatin Calcium / pharmacokinetics ; Rosuvastatin Calcium / pharmacology ; Mice, Inbred C57BL Contributed Indexing: Keywords: Bilirubin; Interplay; Novel mouse model; Plasma exposure; Tissue distribution; Transmembrane drug transporters Substance Nomenclature: 0 (ATP Binding Cassette Transporter, Subfamily G, Member 2) ; RFM9X3LJ49 (Bilirubin) ; 0 (ATP Binding Cassette Transporter, Subfamily B) ; 0 (Organic Anion Transporters) ; 0 (Abcg2 protein, mouse) ; 0 (Liver-Specific Organic Anion Transporter 1) ; E6582LOH6V (fexofenadine) ; 7BA5G9Y06Q (Terfenadine) ; EC 7.6.2.2 (Abcb1b protein, mouse) ; 83MVU38M7Q (Rosuvastatin Calcium) ; 0 (Slco2b1 protein, mouse) Entry Date(s): Date Created: 20240501 Date Completed: 20240602 Latest Revision: 20240610 Update Code: 20240610

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