title: R- and S-Warfarin Were Transported by Breast Cancer Resistance Protein: From In Vitro to Pharmacokinetic-Pharmacodynamic Studies.
abstract: Warfarin, a racemate of R- and S-warfarin, is an important oral anticoagulant with narrow therapeutic window. Being an acidic drug, warfarin (pKa = 4.94) exists mainly as anion under physiological pH. We hypothesized that the transport of warfarin anion across cell membrane was mediated by breast cancer resistance protein (BCRP), an efflux transporter having a variety of acidic substrates. This study aimed at verifying that warfarin was a substrate of BCRP. Cell lines and mice were used for transport assay and pharmacokinetic-pharmacodynamic studies, respectively. The concentrations of R- and S-warfarin were simultaneously determined by liquid chromatography-mass spectrometry method. Transport assay showed that the intracellular concentrations of R- and S-warfarin in MDCKII-BCRP were significantly lower than those in MDCKII. In addition, Ko143, a potent BCRP inhibitor, significantly inhibited the efflux transport of R- and S-warfarin in MDCKII-BCRP, but not in MDCKII. Pharmacokinetic study showed that the plasma concentrations of R- and S-warfarin in Bcrp-/-mice were significantly higher than those in wild-type mice at 6 h after dosing. Anticoagulation measurement showed that the international normalized ratio in Bcrp-/-mice was significantly higher than that in wild-type mice at 24 h after dosing. In conclusion, R- and S-warfarin were transported by BCRP.
authors.affiliation: School of Pharmacy, China Medical University, Taichung, Taiwan 40402, R.O.C.
authors.forename: Meng-Syuan
authors.initials: MS
authors.lastname: Yang
authors.affiliation: Department of Pharmacy, China Medical University Hospital, Taichung, Taiwan 40447, R.O.C.
authors.forename: Chung-Ping
authors.initials: CP
authors.lastname: Yu
authors.affiliation: School of Pharmacy, China Medical University, Taichung, Taiwan 40402, R.O.C.
authors.forename: Pei-Dawn Lee
authors.initials: PL
authors.lastname: Chao
authors.affiliation: School of Pharmacy, China Medical University, Taichung, Taiwan 40402, R.O.C.. Electronic address: splin@mail.cmu.edu.tw.
authors.forename: Shiuan-Pey
authors.initials: SP
authors.lastname: Lin
authors.affiliation: School of Pharmacy, China Medical University, Taichung, Taiwan 40402, R.O.C.; Department of Pharmacy, China Medical University Hospital, Taichung, Taiwan 40447, R.O.C.. Electronic address: hou5133@gmail.com.
authors.forename: Yu-Chi
authors.initials: YC
authors.lastname: Hou
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2 / Q000172:deficiency / Q000378:metabolism*; D000818:Animals; D000925:Anticoagulants / Q000737:chemistry / Q000493:pharmacokinetics; D001692:Biological Transport / Q000187:drug effects / Q000502:physiology; D004285:Dogs; D005260:Female; D006801:Humans; D061985:Madin Darby Canine Kidney Cells; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013237:Stereoisomerism; D014859:Warfarin / Q000737:chemistry* / Q000493:pharmacokinetics*
chemical_list: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; C501412:Abcg2 protein, mouse; D000925:Anticoagulants; D014859:Warfarin
keywords: ABC transporters; drug transport; mass spectrometry; pharmacokinetics/pharmacodynamics; preclinical pharmacokinetics