Evaluation of Organic Anion Transporter 1A2-knock-in Mice as a Model of Human Blood-brain Barrier

Drug Metabolism and Disposition : the Biological Fate of Chemicals
Yamato SanoH Kusuhara

Abstract

The present study aimed to establish a humanized mouse model with which to explore OATP1A2-mediated transcellular transport of drug substrates across the blood-brain barrier (BBB) and to evaluate the usefulness of the humanized mice in preclinical studies. Sulpiride, amisulpride, sultopride, and triptans were used as probes to discriminate OATP1A2 and Oatp1a4. We generated a mouse line humanized for OATP1A2 by introducing the coding region downstream of the Oatp1a4 promoter using the CRISPR/Cas9 technique. In the mice generated, OATP1A2 mRNA in the brain was increased corresponding to disappearance of Oatp1a4. OATP1A2 was localized on both the luminal and abluminal sides of the BBB. Unfortunately, study in vivo employing sulpiride, sumatriptan, and zolmitriptan as probes did not indicate any difference in their brain-to-plasma ratio between the control and humanized mice. Quantitative targeted absolute proteomic analysis of the BBB fraction from the humanized mice revealed that almost all analyzed transporters and membrane proteins were expressed at similar levels to those in control mice. The quantitative levels of OATP1A2 differed depending on the peptide quantified, which suggests that incomplete translation or posttranslati...Continue Reading

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Citations

Oct 20, 2018·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Aarti Sawant-Basak, R Scott Obach
Jan 27, 2019·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Patrick E TrapaJennifer L Liras
Feb 6, 2019·Fluids and Barriers of the CNS·Richard F KeepLester R Drewes
Nov 5, 2020·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Tatsuki MochizukiHiroyuki Kusuhara
May 31, 2019·Biomaterials·Sadhana JacksonMichael M Gottesman

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