Deletion ofAbcg2Has Differential Effects on Excretion and Pharmacokinetics of Probe Substrates in Rats
| Autor: | Bradley K. Wong, Yun Ling, Adria E. Colletti, Liyue Huang, Jonathan Roberts, Eskouhie Tchaparian, Xuhai Be, Meghan Langley, Lixia Jin |
|---|---|
| Rok vydání: | 2012 |
| Předmět: |
Male
Digoxin medicine.medical_specialty animal structures Abcg2 Biological Transport Active Gene Expression Absorption (skin) Pharmacology Real-Time Polymerase Chain Reaction Mass Spectrometry Cell Line Rats Sprague-Dawley Excretion Pharmacokinetics Pregnancy Sulfasalazine Internal medicine Gene expression medicine ATP Binding Cassette Transporter Subfamily G Member 2 Animals Bile ATP Binding Cassette Transporter Subfamily B Member 1 Chromatography High Pressure Liquid biology Chemistry Transporter Rats Endocrinology Nitrofurantoin Injections Intravenous embryonic structures biology.protein RNA Molecular Medicine ATP-Binding Cassette Transporters Female Bile Ducts sense organs Algorithms Gene Deletion medicine.drug |
| Zdroj: | Journal of Pharmacology and Experimental Therapeutics. 343:316-324 |
| ISSN: | 1521-0103 0022-3565 |
| Popis: | 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 by90%. Urinary excretion of compound A was minimal. Systemic clearance in the Abcg2(-/-) rats decreased 22, 43 (p0.05), 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. |
| Databáze: | OpenAIRE |
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