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Deletion of Abcg2 Has Differential Effects on Excretion and Pharmacokinetics of Probe Substrates in Rats.

J Pharmacol Exp Ther. 2012 Aug 6;

Authors: Huang L, Be X, Tchaparian EH, Colletti AE, Roberts J, Langley M, Ling Y, Wong BK, Jin L


This study was designed to characterize breast cancer resistance protein (Bcrp) knockout Abcg2(-/-) rats, and to assess the effect of Abcg2 deletion on the excretion and pharmacokinetic properties of probe substrates. Deletion of the target gene in the Abcg2(-/-) rats was confirmed, while gene expression was unaffected for most of the other transporters and metabolizing enzymes. Biliary excretion of nitrofurantoin, sulfasalazine and compound A accounted for 1.5, 48 and 48% of the dose in the Abcg2(+/+) rats, respectively, whereas it was decreased by 70 to 90% in the Abcg2(-/-) rats. Urinary excretion of nitrofurantoin, a significant elimination pathway, was unaffected in the Abcg2(-/-) rats, whereas renal clearance of sulfasalazine, a minor elimination pathway, was reduced by >90%. Urinary excretion of compound A was minimal. Systemic clearance in the Abcg2(-/-) rats decreased 22, 43 (P<0.05) and 57%, respectively, for nitrofurantoin, sulfasalazine and compound A administered at 1 mg/kg, and 27% for compound A administered at 5 mg/kg. Oral absorption of nitrofurantoin, a compound with high aqueous solubility and good permeability, was not limited by Bcrp. In contrast, the absence of Bcrp led to a 33- and 11-fold increase in oral exposure of sulfasalazine and compound A, respectively. These data show that Bcrp plays a crucial role in biliary excretion of these probe substrates, and has differential effects on systemic clearance and oral absorption in rats depending on clearance mechanisms and compound properties. Abcg2(-/-) rat is a useful model for understanding the role of Bcrp in elimination and oral absorption.

PMID: 22869929 [PubMed - as supplied by publisher]