title: Stereoselective interaction of pantoprazole with ABCG2. I. Drug accumulation in rat milk.
abstract: Active transport of drug into milk is a major concern in breastfeeding. Abcg2 plays a critical role in drug transfer into rat milk, which is consistent with evidence in humans. Although it is estimated that approximately half of all therapeutic agents are chiral, there have been few reports of stereoselective interactions with ABCG2. The purpose of this study was to investigate the interaction of pantoprazole (PAN) isomers with Abcg2 in in vitro and in vivo experiments. Pantoprazole isomer flux was characterized using Abcg2-Madin-Darby canine kidney II (MDCKII) cells in Transwell plates. In a crossover design, Sprague-Dawley lactating rats were used to study PAN accumulation in milk after an intravenous infusion of pantoprazole mixture in the presence/absence of Abcg2 inhibitor [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)]. Samples were analyzed by high-performance liquid chromatography/liquid chromatography-mass spectrometry. The results indicated that pantoprazole isomers were transported in an identical fashion in vector-MDCKII cell lines, whereas a significant difference in flux was observed in Abcg2-MDCKII cell line. The administration of GF120918 slightly increased the concentration of both isomers in serum, but no statistical difference was observed. However, the systemic clearance of (+)PAN (0.57 ± 0.1) was larger than (-)PAN (0.44 ± 0.12) (P < 0.01). Milk to serum ratio (M/S) of (-)PAN (1.36 ± 0.20) was 2.5-fold greater than that of (+)PAN (0.54 ± 0.09) (P < 0.01). Administration of GF120918 decreased M/S of (-)PAN to 0.50 ± 0.08 (P < 0.001) and (+)PAN to 0.38 ± 0.07 (P > 0.05). In conclusion, Abcg2, which is responsible for differential accumulation in milk, interacts stereoselectively with PAN isomers. Stereoselective transport of ABCG2 may have broader consequences in drug disposition.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 South Limestone, Lexington, KY 40536, USA.
authors.forename: Lipeng
authors.initials: L
authors.lastname: Wang
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: McNamara
mesh_terms: D053799:2-Pyridinylmethylsulfinylbenzimidazoles / Q000097:blood / Q000737:chemistry* / Q000493:pharmacokinetics*; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000166:Acridines / Q000494:pharmacology; D000818:Animals; D001693:Biological Transport, Active; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D018592:Cross-Over Studies; D004285:Dogs; D005260:Female; D007262:Infusions, Intravenous; D013058:Mass Spectrometry; D008892:Milk / Q000737:chemistry / Q000378:metabolism*; D000077402:Pantoprazole; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D044005:Tetrahydroisoquinolines / Q000494:pharmacology
chemical_list: D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; C489249:Abcg2 protein, rat; D000166:Acridines; D044005:Tetrahydroisoquinolines; D000077402:Pantoprazole; C083501:Elacridar