RT Journal Article
SR Electronic
T1 Role of OATP2B1 in drug absorption and drug-drug interactions
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP dmd.119.090316
DO 10.1124/dmd.119.090316
A1 Mingqing Chen
A1 Shuiying Hu
A1 Yang Li
A1 Alice A Gibson
A1 Qiang Fu
A1 Sharyn D Baker
A1 Alex Sparreboom
YR 2020
UL http://dmd.aspetjournals.org/content/early/2020/02/28/dmd.119.090316.abstract
AB The organic anion transporting polypeptide OATP2B1 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 HMG-CoA 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. In order 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 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.SIGNIFICANCE STATEMENT The current investigation suggests that OATP2B1-deficient mice 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.