Abstract
Transporter-mediated processes in the lactating mammary gland may explain the significant accumulation of certain drugs in breast milk. The purpose of this study was to identify potential candidate drug transport proteins involved in drug accumulation in milk. Quantitative reverse transcription-polymerase chain reaction methods were developed to determine the relative RNA levels of 30 different drug transporter genes. Transporter gene RNA levels in lactating mammary epithelial cells (MEC) purified from pooled fresh breast milk samples were compared with levels in nonlactating MEC, liver, and kidney tissue. Transcripts were detected in lactating MEC for OCT1, OCT3, OCTN1, OCTN2, OATP-A, OATP-B, OATP-D, OATP-E, MRP1, MRP2, MRP5, MDR1, CNT1, CNT3, ENT1, ENT3, NCBT1, PEPT1, and PEPT2. No transcripts were detected for OCT2, OAT1, OAT2, OAT3, OAT4, OATP-C, MRP3, MRP4, CNT2, ENT2, and NCBT2. Lactating MEC demonstrated more than 4-fold higher RNA levels of OCT1, OCTN1, PEPT2, CNT1, CNT3, and ENT3, and more than 4-fold lower RNA levels of MDR1 and OCTN2 relative to nonlactating MEC. Lactating MEC showed significantly higher RNA levels of CNT3 relative to liver and kidney, increased PEPT2 RNA levels relative to liver, and increased OATP-A RNA levels relative to kidney. These data imply CNT3 may play a specialized role in nucleoside accumulation in milk and may identify an important role for PEPT2 and OATP-A transporters at the lactating mammary epithelium. Furthermore, transporters expressed in lactating MEC identify a potential role for these transporters in drug disposition at the mammary gland.
Footnotes
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The University of Kentucky Research Challenge Trust Fund provided financial support for J.A. This work was supported by National Institutes of Health Grant HD37463.
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DOI: 10.1124/jpet.102.038315
- Abbreviations:
- M/S
- milk drug concentration to serum drug concentration ratio
- OCT
- organic cation transporter
- OAT
- organic anion transporter
- OATP
- organic anion transporting polypeptide
- MRP
- multidrug resistance-associated protein
- MDR
- multidrug resistance transporter
- MEC
- mammary epithelial cells
- RT-PCR
- reverse transcription-polymerase chain reaction
- FBS
- fetal bovine serum
- PBS
- phosphate-buffered saline
- EMA
- epithelial membrane antigen
- MPC
- magnetic particle concentrator
- CALLA
- common acute lymphoblastic leukemia antigen
- CNT
- concentrative nucleoside transporter
- ENT
- equilibrative nucleoside transporter
- NCBT
- nucleobase transporter
- OCTN
- organic cation/carnitine transporter
- PEPT
- oligopeptide transporter
- Received May 2, 2002.
- Accepted June 25, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
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