Journal
XENOBIOTICA
Volume 48, Issue 5, Pages 467-477Publisher
TAYLOR & FRANCIS LTD
DOI: 10.1080/00498254.2017.1328147
Keywords
BCRP inhibitor; Bcrp knockout; Ko143 analog; ML753286; Preclinical ADME characterization
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1.Breast cancer resistance protein (BCRP) plays an important role in drug absorption, distribution and excretion. It is challenging to evaluate BCRP functions in preclinical models because commonly used BCRP inhibitors are nonspecific or unstable in animal plasma.2.In this work, in vitro absorption, distribution, metabolism and elimination (ADME) assays and pharmacokinetic (PK) experiments in Bcrp knockout (KO) (Abcg2(-/-)) and wild-type (WT) FVB mice and Wistar rats were conducted to characterize the preclinical properties of a novel selective BCRP inhibitor (ML753286, a Ko143 analog).3.ML753286 is a potent inhibitor for BCRP, but not for P-glycoprotein (P-gp), organic anion-transporting polypeptide (OATP) or major cytochrome P450s (CYPs). It has high permeability, but is not an efflux transporter substrate. ML753286 has low to medium clearance in rodent and human liver S9 fractions, and is stable in plasma cross species. Bcrp inhibition affects oral absorption and clearance of sulfasalazine in rodents. A single dose of ML753286 at 50-300mg/kg orally, and at 20mg/kg intravenously or 25mg/kg orally inhibits Bcrp functions in mice and rats, respectively.4.These findings confirm that ML753286 is a useful selective inhibitor to evaluate BCRP/Bcrp activity in vitro and in rodent model systems.
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