TY - JOUR
T1 - Organic anion-transporting polypeptide 2B1 knockout and humanized mice; insights into the handling of bilirubin and drugs
AU - Li, Wenlong
AU - Iusuf, Dilek
AU - Sparidans, Rolf W.
AU - Wagenaar, Els
AU - Wang, Yaogeng
AU - de Waart, Dirk R.
AU - Martins, Margarida L. F.
AU - van Hoppe, Stéphanie
AU - Lebre, Maria C.
AU - van Tellingen, Olaf
AU - Beijnen, Jos H.
AU - Schinkel, Alfred H.
N1 - Funding Information: This work was funded in part by the China Scholarship Council (to WL and YW), Dutch Cancer Society (to DI), and DiacetylM BV (to MM). We gratefully acknowledge the support from the Transgenic Facility and Genomic Core Facility of the Netherlands Cancer Institute in developing genetically modified mouse models and performing RNA sequencing analysis, respectively. 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 at the Netherlands Cancer Institute. Publisher Copyright: © 2023 The Authors
PY - 2023/4/1
Y1 - 2023/4/1
N2 - Organic anion transporting polypeptide 2B1 (OATP2B1/SLCO2B1) facilitates uptake transport of structurally diverse endogenous and exogenous compounds. To investigate the roles of OATP2B1 in physiology and pharmacology, we established and characterized Oatp2b1 knockout (single Slco2b1-/- and combination Slco1a/1b/2b1-/-) and humanized hepatic and intestinal OATP2B1 transgenic mouse models. While viable and fertile, these strains exhibited a modestly increased body weight. In males, unconjugated bilirubin levels were markedly reduced in Slco2b1-/- compared to wild-type mice, whereas bilirubin monoglucuronide levels were modestly increased in Slco1a/1b/2b1-/- compared to Slco1a/1b-/- mice. Single Slco2b1-/- mice showed no significant changes in oral pharmacokinetics of several tested drugs. However, markedly higher or lower plasma exposure of pravastatin and the erlotinib metabolite OSI-420, respectively, were found in Slco1a/1b/2b1-/- compared to Slco1a/1b-/- mice, while oral rosuvastatin and fluvastatin behaved similarly between the strains. In males, humanized OATP2B1 strains showed lower conjugated and unconjugated bilirubin levels than control Slco1a/1b/2b1-deficient mice. Moreover, hepatic expression of human OATP2B1 partially or completely rescued the impaired hepatic uptake of OSI-420, rosuvastatin, pravastatin, and fluvastatin in Slco1a/1b/2b1-/- mice, establishing an important role in hepatic uptake. Expression of human OATP2B1 in the intestine was basolateral and markedly reduced the oral availability of rosuvastatin and pravastatin, but not of OSI-420 and fluvastatin. Neither lack of Oatp2b1, nor overexpression of human OATP2B1 had any effect on fexofenadine oral pharmacokinetics. While these mouse models still have limitations for human translation, with additional work we expect they will provide powerful tools to further understand the physiological and pharmacological roles of OATP2B1.
AB - Organic anion transporting polypeptide 2B1 (OATP2B1/SLCO2B1) facilitates uptake transport of structurally diverse endogenous and exogenous compounds. To investigate the roles of OATP2B1 in physiology and pharmacology, we established and characterized Oatp2b1 knockout (single Slco2b1-/- and combination Slco1a/1b/2b1-/-) and humanized hepatic and intestinal OATP2B1 transgenic mouse models. While viable and fertile, these strains exhibited a modestly increased body weight. In males, unconjugated bilirubin levels were markedly reduced in Slco2b1-/- compared to wild-type mice, whereas bilirubin monoglucuronide levels were modestly increased in Slco1a/1b/2b1-/- compared to Slco1a/1b-/- mice. Single Slco2b1-/- mice showed no significant changes in oral pharmacokinetics of several tested drugs. However, markedly higher or lower plasma exposure of pravastatin and the erlotinib metabolite OSI-420, respectively, were found in Slco1a/1b/2b1-/- compared to Slco1a/1b-/- mice, while oral rosuvastatin and fluvastatin behaved similarly between the strains. In males, humanized OATP2B1 strains showed lower conjugated and unconjugated bilirubin levels than control Slco1a/1b/2b1-deficient mice. Moreover, hepatic expression of human OATP2B1 partially or completely rescued the impaired hepatic uptake of OSI-420, rosuvastatin, pravastatin, and fluvastatin in Slco1a/1b/2b1-/- mice, establishing an important role in hepatic uptake. Expression of human OATP2B1 in the intestine was basolateral and markedly reduced the oral availability of rosuvastatin and pravastatin, but not of OSI-420 and fluvastatin. Neither lack of Oatp2b1, nor overexpression of human OATP2B1 had any effect on fexofenadine oral pharmacokinetics. While these mouse models still have limitations for human translation, with additional work we expect they will provide powerful tools to further understand the physiological and pharmacological roles of OATP2B1.
KW - Bilirubin
KW - Bilirubin (PubChem CID: 5280352)
KW - Bilirubin diglucuronode (PubChem CID: 5280817)
KW - Drug disposition
KW - Erlotinib (PubChem CID: 176870)
KW - Fexofenadine (PubChem CID: 3348)
KW - Fluvastatin (PubChem CID: 446155)
KW - Genetically modified mouse models
KW - OSI-413 (PubChem CID: 18925012)
KW - OSI-420 (10317566)
KW - Oral availability
KW - Organic anion-transporting polypeptide 2B1
KW - Pravastatin (PubChem CID: 54687)
KW - Rosuvastatin (PubChem CID: 446157)
KW - Tissue distribution
UR - http://www.scopus.com/inward/record.url?scp=85150232745&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.phrs.2023.106724
DO - https://doi.org/10.1016/j.phrs.2023.106724
M3 - Article
C2 - 36907287
SN - 1043-6618
VL - 190
JO - Pharmacological Research
JF - Pharmacological Research
M1 - 106724
ER -