Role of Oatp2b1 in Drug Absorption and Drug-Drug Interactions

The organic anion transporting polypeptide (OATP)2B1 is localized on the basolateral membrane of hepatocytes and is expressed in enterocytes. Based on its distribution pattern and functional similarity to OATP1B-type transporters, OATP2B1 might have a role in the absorption and disposition of a rang...

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Veröffentlicht in:Drug metabolism and disposition 2020-05, Vol.48 (5), p.419-425
Hauptverfasser: Chen, Mingqing, Hu, Shuiying, Li, Yang, Gibson, Alice A., Fu, Qiang, Baker, Sharyn D., Sparreboom, Alex
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container_end_page 425
container_issue 5
container_start_page 419
container_title Drug metabolism and disposition
container_volume 48
creator Chen, Mingqing
Hu, Shuiying
Li, Yang
Gibson, Alice A.
Fu, Qiang
Baker, Sharyn D.
Sparreboom, Alex
description The organic anion transporting polypeptide (OATP)2B1 is localized on the basolateral membrane of hepatocytes and is expressed in enterocytes. Based on its distribution pattern and functional similarity to OATP1B-type transporters, OATP2B1 might have a role in the absorption and disposition of a range of xenobiotics. Although several prescription drugs, including hydroxymethylglutaryl-coenzyme A-CoA reductase inhibitors (statins) such as fluvastatin, are OATP2B1 substrates in vitro, evidence supporting the in vivo relevance of this transporter remains limited, and most has relied on substrate-inhibitor interactions resulting in altered pharmacokinetic properties of the victim drugs. To address this knowledge deficit, we developed and characterized an Oatp2b1-deficient mouse model and evaluated the impact of this transporter on the absorption and disposition of fluvastatin. Consistent with the intestinal localization of Oatp2b1, we found that the genetic deletion or pharmacological inhibition of Oatp2b1 was associated with decreased absorption of fluvastatin by 2- to 3-fold. The availability of a viable Oatp2b1-deficient mouse model provides an opportunity to unequivocally determine the contribution of this transporter to the absorption and drug-drug interaction potential of drugs. The current investigation suggests that mice deficient in Oatp2b1 provide a valuable tool to study the in vivo importance of this transporter. In addition, our studies have identified novel potent inhibitors of OATP2B1 among the class of tyrosine kinase inhibitors, a rapidly expanding class of drugs used in various therapeutic areas that may cause drug-drug interactions with OATP2B1 substrates.
doi_str_mv 10.1124/dmd.119.090316
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subjects Administration, Oral
Animals
Drug Interactions
Female
Fluvastatin - administration & dosage
Fluvastatin - pharmacokinetics
HEK293 Cells
Humans
Hydroxymethylglutaryl-CoA Reductase Inhibitors - administration & dosage
Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacokinetics
Intestinal Absorption
Intestinal Mucosa - metabolism
Male
Mice
Mice, Knockout
Organic Anion Transporters - genetics
Organic Anion Transporters - metabolism
RNA - genetics
RNA - metabolism
title Role of Oatp2b1 in Drug Absorption and Drug-Drug Interactions
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