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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Interactions between Cimetidine, Nitrofurantoin, and Probenecid Active Transport into Rat Milk

Phillip M. Gerk, Cheah Y. Oo, Earl W. Paxton, Jeffrey A. Moscow and Patrick J. McNamara
Journal of Pharmacology and Experimental Therapeutics January 2001, 296 (1) 175-180;
Phillip M. Gerk
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Cheah Y. Oo
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Earl W. Paxton
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Jeffrey A. Moscow
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Patrick J. McNamara
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Abstract

The purpose of these studies was to further elucidate the active mammary epithelial transport processes for the organic cation cimetidine and the organic anion nitrofurantoin and to determine which of the identified rat organic anion (rOATs) and organic cation (rOCTs) transporters may be responsible for transport of these drugs into milk. Milk-to-serum ratios (M/S) were predicted in vitro for nitrofurantoin,p-aminohippurate (PAH), and probenecid, and were compared with the observed M/S values. Groups of six lactating female rats received intravenous infusions of cimetidine, nitrofurantoin, PAH, or probenecid alone and with another agent. Steady-state milk and serum concentrations were measured by high performance liquid chromatography. Reverse transcriptase-polymerase chain reaction was performed to detect rOATs and rOCTs in livers, kidneys, and mammary glands of lactating rats. Nitrofurantoin and probenecid were actively transported into rat milk with an M/S 100- and 4.7-fold greater than predicted, respectively, but predicted and observed M/S values for PAH were similar. The cimetidine infusion did not alter nitrofurantoin M/S. Nitrofurantoin significantly decreased M/S of cimetidine (26.6 ± 4.9 versus 17.7 ± 5.6). Probenecid did not alter the M/S of nitrofurantoin, or PAH, but increased the M/S of cimetidine from 15.5 ± 3.6 to 21.5 ± 7.7. Of the six transporter genes, evidence of expression in lactating rat mammary tissue was found for only rOCT1 and rOCT3. The results suggest different secretory transport systems for cimetidine, nitrofurantoin, and probenecid, but that passive diffusion governs PAH passage into milk. The products of rOCT1 and rOCT3 might transport these drugs into milk.

Footnotes

  • Send reprint requests to: Patrick J. McNamara, Ph.D., Rm. 401A Pharmacy Bldg., University of Kentucky College of Pharmacy, Lexington, KY 40536-0082. E-mail: pmcnamar{at}pop.uky.edu

  • This work was supported by National Institutes of Health Grant GM38836 and the University of Kentucky Women's Health Initiative. This article was previously presented in part in two abstracts by Gerk et al. (1997, 1998).

  • Abbreviations:
    M/S
    milk-to-serum concentration ratio
    LMEDT
    lactating mammary epithelium drug transport
    rOAT
    rat organic anion transporter
    rOCT
    rat organic cation transporter
    RT-PCR
    reverse transcriptase-polymerase chain reaction
    HPLC
    high performance liquid chromatography
    fus
    un-ionized fraction of the drug in serum
    fum
    un-ionized fraction of the drug in milk
    fs
    unbound fraction in serum
    fm
    unbound fraction in milk
    Cls
    systemic clearance
    PAH
    p-aminohippurate
    • Received June 16, 2000.
    • Accepted September 13, 2000.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 296 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 296, Issue 1
1 Jan 2001
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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Interactions between Cimetidine, Nitrofurantoin, and Probenecid Active Transport into Rat Milk

Phillip M. Gerk, Cheah Y. Oo, Earl W. Paxton, Jeffrey A. Moscow and Patrick J. McNamara
Journal of Pharmacology and Experimental Therapeutics January 1, 2001, 296 (1) 175-180;

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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Interactions between Cimetidine, Nitrofurantoin, and Probenecid Active Transport into Rat Milk

Phillip M. Gerk, Cheah Y. Oo, Earl W. Paxton, Jeffrey A. Moscow and Patrick J. McNamara
Journal of Pharmacology and Experimental Therapeutics January 1, 2001, 296 (1) 175-180;
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