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.
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 microg/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.
Wang
Lipeng
L
Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 725 Rose Street, Lexington, KY 40536, USA.
Leggas
Markos
M
Goswami
Mamta
M
Empey
Philip E
PE
McNamara
Patrick J
PJ
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D000166:Acridines / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001562:Benzimidazoles / Q000378:metabolism; D001693:Biological Transport, Active / Q000187:drug effects; D002460:Cell Line; D004285:Dogs; D005260:Female; D005456:Fluorescent Dyes; D007262:Infusions, Intravenous; D007668:Kidney / Q000378:metabolism; D007774:Lactation / Q000378:metabolism*; D008321:Mammary Glands, Animal / Q000187:drug effects / Q000378:metabolism; D008892:Milk / Q000378:metabolism*; D009582:Nitrofurantoin / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000378:metabolism; D044005:Tetrahydroisoquinolines / Q000008:administration & dosage / Q000494:pharmacology*; D014162:Transfection
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; D000166:Acridines; D001562:Benzimidazoles; D005456:Fluorescent Dyes; D011994:Recombinant Proteins; D044005:Tetrahydroisoquinolines; D009582:Nitrofurantoin; C083501:Elacridar; C017807:bisbenzimide ethoxide trihydrochloride
J Acquir Immune Defic Syndr Hum Retrovirol. 1998 Nov 1;19(3):203-9
9803961
Bioorg Med Chem. 2007 Apr 15;15(8):2892-7
17317193
AAPS J. 2005 May 11;7(1):E118-33
16146333
Cancer Res. 2004 May 1;64(9):3296-301
15126373
J Clin Invest. 1998 Jan 15;101(2):289-94
9435299
Drug Metab Dispos. 2007 Jul;35(7):1165-73
17437964
Adv Exp Med Biol. 2001;501:547-52
11787727
Clin Cancer Res. 2007 Jun 1;13(11):3276-85
17545533
Kidney Int. 2008 Jan;73(2):220-5
17978814
Mol Pharmacol. 2005 May;67(5):1758-64
15709111
J Pharmacol Exp Ther. 2004 Jul;310(1):334-41
15007102
J Pediatr Surg. 2002 Nov;37(11):1579-84
12407543
Cancer Res. 2006 May 1;66(9):4802-7
16651435
J Pharmacol Exp Ther. 2002 Nov;303(2):487-96
12388627
J Pharmacol Exp Ther. 1988 Mar;244(3):919-24
3252037
Pharm Res. 2002 Mar;19(3):299-305
11934237
Biochim Biophys Acta. 2002 Sep 20;1565(1):6-16
12225847
J Pharmacol Exp Ther. 1997 Feb;280(2):669-76
9023278
Cancer Res. 2005 Jun 1;65(11):4852-60
15930306
Drug Metab Dispos. 2008 Feb;36(2):452-60
17967933
J Pharmacol Exp Ther. 2001 Jan;296(1):175-80
11123378
J Pharm Sci. 1987 Mar;76(3):189-93
3585733
Toxicol Appl Pharmacol. 1991 Jun 1;109(1):149-60
2038745
Drug Metab Dispos. 2007 Feb;35(2):268-74
17093006
Biochemistry. 1997 Nov 18;36(46):14218-27
9369495
Drug Metab Dispos. 2007 Dec;35(12):2154-8
17785426
Drug Metab Dispos. 1992 Mar-Apr;20(2):302-8
1352225
J Pharmacol Exp Ther. 1988 Mar;244(3):925-8
3252038
Cancer Chemother Pharmacol. 2005 Jan;55(1):91-9
15565444
Pharmacotherapy. 2001 Jun;21(6):669-75
11401180
Antimicrob Agents Chemother. 2005 Apr;49(4):1626-8
15793156
J Pharmacol Exp Ther. 2006 May;317(2):579-89
16421286
Drug Metab Dispos. 2006 Apr;34(4):556-62
16204465
Biochemistry. 1998 Mar 17;37(11):3594-601
9530286
Curr Opin Oncol. 2000 Sep;12(5):450-8
10975553