title: Deletion of Abcg2 has differential effects on excretion and pharmacokinetics of probe substrates in rats.
abstract: 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 >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. The Abcg2(-/-) rat is a useful model for understanding the role of Bcrp in elimination and oral absorption.
authors.affiliation: Pharmacokinetics and Drug Metabolism, Amgen Inc., 360 Binney Street, Cambridge, MA 02142, USA. liyueh@amgen.com
authors.forename: Liyue
authors.initials: L
authors.lastname: Huang
authors.forename: Xuhai
authors.initials: X
authors.lastname: Be
authors.forename: Eskouhie H
authors.initials: EH
authors.lastname: Tchaparian
authors.forename: Adria E
authors.initials: AE
authors.lastname: Colletti
authors.forename: Jonathan
authors.initials: J
authors.lastname: Roberts
authors.forename: Meghan
authors.initials: M
authors.lastname: Langley
authors.forename: Yun
authors.initials: Y
authors.lastname: Ling
authors.forename: Bradley K
authors.initials: BK
authors.lastname: Wong
authors.forename: Lixia
authors.initials: L
authors.lastname: Jin
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000502:physiology*; D000465:Algorithms; D000818:Animals; D001646:Bile / Q000378:metabolism; D001652:Bile Ducts / Q000502:physiology; D001693:Biological Transport, Active / Q000235:genetics / Q000502:physiology; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D004077:Digoxin / Q000493:pharmacokinetics; D005260:Female; D017353:Gene Deletion; D015870:Gene Expression / Q000187:drug effects; D007275:Injections, Intravenous; D008297:Male; D013058:Mass Spectrometry; D009582:Nitrofurantoin / Q000493:pharmacokinetics; D010599:Pharmacokinetics; D011247:Pregnancy; D012313:RNA / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D012460:Sulfasalazine / Q000493:pharmacokinetics
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; C489249:Abcg2 protein, rat; D012460:Sulfasalazine; D012313:RNA; D004077:Digoxin; D009582:Nitrofurantoin