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Uremic toxins inhibit hepatic uptake of eprosartan
Author(s) -
Sun H.,
Huang Y.,
Okochi H.,
Frassetto L.,
Benet L. Z.
Publication year - 2005
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2004.11.012
Subject(s) - chemistry , efflux , transporter , pharmacology , ic50 , uremic toxins , endocrinology , hepatocyte , medicine , in vivo , in vitro , biochemistry , kidney disease , biology , gene , microbiology and biotechnology
Background Hepatic clearance of eprosartan (Epr) is significantly decreased in patients with end stage renal disease (ESRD). Uremic toxins may directly inhibit the transporter‐mediated uptake and efflux thereby reducing hepatic clearance of Epr, which is not metabolized by CYPs. Methods The inhibitory effects of the uremic toxins, CMPF and indoxyl sulfate, on uptake transporters (rOatp2 and hOATP‐C) and the efflux transporter (P‐gp) were examined using transient transfected HEK293 cells and MDR1‐MDCK cells, respectively. The effects of these uremic toxins on Epr uptake were further evaluated in rat hepatocytes and hOATP‐C transfected cells. Results Both CMPF and indoxyl sulfate exhibited dose‐dependent inhibition of rOatp2 and hOATP‐C. The IC 50 s of CMPF on rOatp2 and hOATP‐C mediated uptake of estrone sulfate (1 μM) were 25 μM and 55 μM, respectively. Indoxyl sulfate is a weaker inhibitor of rOatp2 and hOATP‐C with IC 50 s of 97 μM and 397 μM, respectively. Both uremic toxins had no effects on P‐gp. The uptake of Epr was mainly mediated by rOatp2 in rat. At 200μM, CMPF significantly inhibited Epr uptake by 53% in rat hepatocytes. The uptake of Epr was mediated by OATP‐C in human hepatocytes with a K m value of 12.5± 0.3 μM. CMPF dose‐dependently inhibited Epr (5 μM) uptake by hOATP‐C with an IC 50 of 125.9± 1.3 μM. Conclusion Our study suggests that the inhibitory effect of CMPF may at least partially contribute to the reduced hepatic clearance of Epr in ESRD patients. Clinical Pharmacology & Therapeutics (2005) 77 , P2–P2; doi: 10.1016/j.clpt.2004.11.012