PT - JOURNAL ARTICLE AU - Liyue Huang AU - Xuhai Be AU - Eskouhie H. Tchaparian AU - Adria E. Colletti AU - Jonathan Roberts AU - Meghan Langley AU - Yun Ling AU - Bradley K. Wong AU - Lixia Jin TI - Deletion of <em>Abcg2</em> Has Differential Effects on Excretion and Pharmacokinetics of Probe Substrates in Rats AID - 10.1124/jpet.112.197046 DP - 2012 Nov 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 316--324 VI - 343 IP - 2 4099 - http://jpet.aspetjournals.org/content/343/2/316.short 4100 - http://jpet.aspetjournals.org/content/343/2/316.full SO - J Pharmacol Exp Ther2012 Nov 01; 343 AB - 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-4H-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 &gt;90%. Urinary excretion of compound A was minimal. Systemic clearance in the Abcg2(−/−) rats decreased 22, 43 (p &lt; 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. The Abcg2(−/−) rat is a useful model for understanding the role of Bcrp in elimination and oral absorption.