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

This study was designed to characterize breast cancer resistance protein (Bcrp) knockout Abcg2 (−/−) rats and assess the effect of ATP-binding cassette subfamily G member 2 ( Abcg2 ) deletion on the excretion and pharmacokinetic properties of probe substrates. Deletion of the target gene in the Abcg2 (−/−) rats was confirmed, whereas gene expression was unaffected for most of the other transporters and metabolizing enzymes. Biliary excretion of nitrofurantoin, sulfasalazine, and compound A [2-(5-methoxy-2-((2-methyl-1,3-benzothiazol-6-yl)amino)-4-pyridinyl)-1,5,6,7-tetrahydro-4 H -pyrrolo[3,2-c]pyridin-4-one] 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 Abcg2 (−/−) rat is a useful model for understanding the role of Bcrp in elimination and oral absorption.