title: Prediction of Drug Transfer into Milk Considering Breast Cancer Resistance Protein (BCRP)-Mediated Transport.
abstract: OBJECTIVE
  Drug transfer into milk is of concern due to the unnecessary exposure of infants to drugs. Proposed prediction methods for such transfer assume only passive drug diffusion across the mammary epithelium. This study reorganized data from the literature to assess the contribution of carrier-mediated transport to drug transfer into milk, and to improve the predictability thereof.
  
  
  METHODS
  Milk-to-plasma drug concentration ratios (M/Ps) in humans were exhaustively collected from the literature and converted into observed unbound concentration ratios (M/Punbound,obs). The ratios were also predicted based on passive diffusion across the mammary epithelium (M/Punbound,pred). An in vitro transport assay was performed for selected drugs in breast cancer resistance protein (BCRP)-expressing cell monolayers.
  
  
  RESULTS
  M/Punbound,obs and M/Punbound,pred values were compared for 166 drugs. M/Punbound,obs values were 1.5 times or more higher than M/Punbound,pred values for as many as 13 out of 16 known BCRP substrates, reconfirming BCRP as the predominant transporter contributing to secretory transfer of drugs into milk. Predictability of M/P values for selected BCRP substrates and non-substrates was improved by considering in vitro-evaluated BCRP-mediated transport relative to passive diffusion alone.
  
  
  CONCLUSIONS
  The current analysis improved the predictability of drug transfer into milk, particularly for BCRP substrates, based on an exhaustive data overhaul followed by focused in vitro transport experimentation.
authors.affiliation: Department of Pediatrics, the University of Tokyo Hospital, Faculty of Medicine, the University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Ito
authors.forename: Kousei
authors.initials: K
authors.lastname: Ito
authors.forename: Yuki
authors.initials: Y
authors.lastname: Ikebuchi
authors.forename: Yu
authors.initials: Y
authors.lastname: Toyoda
authors.forename: Tappei
authors.initials: T
authors.lastname: Takada
authors.forename: Akihiro
authors.initials: A
authors.lastname: Hisaka
authors.forename: Akira
authors.initials: A
authors.lastname: Oka
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Suzuki
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000465:Algorithms; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics; D001940:Breast / Q000378:metabolism; D004058:Diffusion; D004285:Dogs; D004848:Epithelium / Q000378:metabolism; D005260:Female; D006801:Humans; D006863:Hydrogen-Ion Concentration; D061985:Madin Darby Canine Kidney Cells; D008895:Milk, Human / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000378:metabolism*; D004364:Pharmaceutical Preparations / Q000378:metabolism*
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; D004364:Pharmaceutical Preparations