RT Journal Article SR Electronic T1 N-(4-[2-(1,2,3,4-Tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]-phenyl)-9,10-dihydro-5-methoxy-9-oxo-4-acridine Carboxamide (GF120918) As a Chemical ATP-Binding Cassette Transporter Family G Member 2 (Abcg2) Knockout Model to Study Nitrofurantoin Transfer into Milk JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP 2591 OP 2596 DO 10.1124/dmd.108.021980 VO 36 IS 12 A1 Wang, Lipeng A1 Leggas, Markos A1 Goswami, Mamta A1 Empey, Philip E. A1 McNamara, Patrick J. YR 2008 UL http://dmd.aspetjournals.org/content/36/12/2591.abstract AB Genetic knockout mice studies suggested ATP-binding cassette transporter family G member 2 (ABCG2)/Abcg2 translocates nitrofurantoin at the mammary-blood barrier, resulting in drug accumulation in milk. The purpose of this study was to establish the role of Abcg2 in nitrofurantoin accumulation in rat milk using N-(4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]-phenyl)-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide (GF120918) as a “chemical knockout” equivalent. The inhibitory effect of GF120918 was verified in Madin-Darby canine kidney II cells stably expressing rat Abcg2 with Hoechst 33342 and nitrofurantoin flux in Transwells. Nitrofurantoin was infused (0.5 mg/h) in the absence and presence of GF120918 (10 mg/kg in dimethyl sulfoxide) to Sprague-Dawley lactating female rats using a balanced crossover design. Administration of GF120918 increased nitrofurantoin concentration in serum (from 443 ± 51 to 650 ± 120 ng/ml) and decreased concentration in milk (from 18.1 ± 0.9 to 1.9 ± 1.2 μg/ml), resulting in corresponding mean values for milk to serum concentration ratio (M/S) of 41.4 ± 19.1 versus 3.04 ± 2.27 in the absence and presence of GF120918 (p < 0.05), respectively. There was a decrease in systemic clearance with GF120918 (2.8 ± 0.5 l/h/kg) compared with vehicle controls (4.1 ± 0.5 l/h/kg; p < 0.05). Western blot analysis revealed good expression of Abcg2 and no P-glycoprotein (P-gp) expression in mammary gland, whereas immunohistochemistry confirmed the apical expression of Abcg2 in lactating mammary gland epithelia. Nitrofurantoin active transport into rat milk can be inhibited by GF120918 resulting in a 10-fold lower M/S. Although GF120918 inhibits both Abcg2 and P-gp, the high expression of Abcg2 and the absence of detectable P-gp expression in lactating mammary gland validate an important role for Abcg2 in nitrofurantoin accumulation in rat milk. GF120918 is particularly useful as a rat chemical knockout model to establish ABCG2's role in drug transfer into milk during breastfeeding. The American Society for Pharmacology and Experimental Therapeutics