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

Autor: Li W; The Netherlands Cancer Institute, Division of Pharmacology, Plesmanlaan 121, Amsterdam 1066 CX, the Netherlands; The Second Affiliated Hospital of Nantong University, Shengli Rd 666, Nantong 226001, China. Electronic address: Wenlong.Li@cruk.cam.ac.uk., Sparidans RW; Utrecht University, Faculty of Science, Department of Pharmaceutical Sciences, Division of Pharmacology, Universiteitsweg 99, Utrecht 3584 CG, the Netherlands., Wang Y; The Netherlands Cancer Institute, Division of Pharmacology, Plesmanlaan 121, Amsterdam 1066 CX, the Netherlands., Martins MLF; The Netherlands Cancer Institute, Division of Pharmacology, Plesmanlaan 121, Amsterdam 1066 CX, the Netherlands., de Waart DR; Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, Meibergdreef 71, Amsterdam 1105 BK, the Netherlands., van Tellingen O; The Netherlands Cancer Institute, Division of Pharmacology, Plesmanlaan 121, Amsterdam 1066 CX, the Netherlands., Song JY; The Netherlands Cancer Institute, Division of Experimental Animal Pathology, Plesmanlaan 121, Amsterdam 1066 CX, the Netherlands., Lebre MC; The Netherlands Cancer Institute, Division of Pharmacology, Plesmanlaan 121, Amsterdam 1066 CX, the Netherlands., van Hoppe S; The Netherlands Cancer Institute, Division of Pharmacology, Plesmanlaan 121, Amsterdam 1066 CX, the Netherlands., Wagenaar E; The Netherlands Cancer Institute, Division of Pharmacology, Plesmanlaan 121, Amsterdam 1066 CX, the Netherlands., Beijnen JH; The Netherlands Cancer Institute, Division of Pharmacology, Plesmanlaan 121, Amsterdam 1066 CX, the Netherlands; Utrecht University, Faculty of Science, Department of Pharmaceutical Sciences, Division of Pharmacoepidemiology & Clinical Pharmacology, Universiteitsweg 99, Utrecht 3584 CG, the Netherlands; The Netherlands Cancer Institute, Department of Pharmacy & Pharmacology, Plesmanlaan 121, Amsterdam 1066 CX, the Netherlands., Schinkel AH; The Netherlands Cancer Institute, Division of Pharmacology, Plesmanlaan 121, Amsterdam 1066 CX, the Netherlands.
Jazyk: angličtina
Zdroj: Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie [Biomed Pharmacother] 2024 Jun; Vol. 175, pp. 116644. Date of Electronic Publication: 2024 Apr 30.
DOI: 10.1016/j.biopha.2024.116644
Abstrakt: 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.
(Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: