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Research ArticleArticle

Pharmacokinetic Interaction between JBP485 and Cephalexin in Rats

Jian Zhang, Changyuan Wang, Qi Liu, Qiang Meng, Jian Cang, Huijun Sun, Ying Gao, Taiichi Kaku and Kexin Liu
Drug Metabolism and Disposition June 2010, 38 (6) 930-938; DOI: https://doi.org/10.1124/dmd.110.032060
Jian Zhang
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Changyuan Wang
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Qi Liu
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Qiang Meng
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Jian Cang
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Huijun Sun
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Ying Gao
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Taiichi Kaku
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Kexin Liu
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Abstract

The purpose of this study was to investigate the pharmacokinetic mechanism of interaction between JBP485 (cyclo-trans-4-l-hydroxyprolyl-l-serine, a dipeptide) and cephalexin when they were coadministered in rats. The plasma concentrations of JBP485 and cephalexin were both decreased significantly after oral combination, but little difference was observed after simultaneous intravenous administration of the two agents, suggesting that the interaction target localized in the intestine during the absorption process. The uptake in everted intestinal sacs and absorption in jejunal perfusions of JBP485 and cephalexin were dramatically reduced after drug combination. When JBP485 and cephalexin were coadministered, both the decrease in accumulative renal excretion (81.9–68.1% of JBP485 and 91.8–74.5% of cephalexin) and in renal clearance (2.89–1.87 ml/min/kg JBP485 and 2.23–1.58 ml/min/kg cephalexin) indicated that transporter(s) other than H+/peptide transporter (PEPT) 2 are involved in the process of excretion. Probenecid could reduce renal excretion of JBP485 and cephalexin. Moreover, the decreased uptake of JBP485 with probenecid, p-aminohippuate, or benzylpenicillin in kidney slices could be explained by an inhibition in the kidney via organic anion transporters (OATs), at least in part. The accumulation of JBP485 in human (h) OAT1- or hOAT3-human embryonic kidney (HEK) 293 cells was greater than that in vector-HEK293 cells, and the uptake could be inhibited by probenecid. These findings further confirmed that the pharmacokinetic mechanism of the drug-drug interaction between JBP485 and cephalexin could be explained by their inhibition of the same transporters in the intestinal mucosa (PEPT1) and kidneys (PEPT2 and OATs). We provide the first evidence that JBP485 is not only a substrate of PEPTs but also is excreted through OATs.

Footnotes

  • This work was supported by the National Natural Science Foundation of China [Grants 30672498 and 30873118]; and the Liaoning Provincial Key Laboratory [Grant 2008S078].

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

    doi:10.1124/dmd.110.032060.

  • ABBREVIATIONS:

    PEPT
    peptide transporter
    JBP485
    cyclo-trans-4-l-hydroxyprolyl-l-serine
    Gly-sar
    glycylsarcosine
    OAT
    organic anion transporter
    LC-MS/MS
    liquid chromatography-tandem mass spectrometry
    PAH
    p-aminohippuate
    PCG
    benzylpenicillin
    h
    human
    HEK
    human embryonic kidney
    KRB
    Krebs-Ringer bicarbonate
    HBSS
    Hanks' balanced salt solution
    AUC
    area under the plasma concentration-time curve.

  • Received January 5, 2010.
  • Accepted March 10, 2010.
  • Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 38 (6)
Drug Metabolism and Disposition
Vol. 38, Issue 6
1 Jun 2010
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Research ArticleArticle

Pharmacokinetic Interaction between JBP485 and Cephalexin in Rats

Jian Zhang, Changyuan Wang, Qi Liu, Qiang Meng, Jian Cang, Huijun Sun, Ying Gao, Taiichi Kaku and Kexin Liu
Drug Metabolism and Disposition June 1, 2010, 38 (6) 930-938; DOI: https://doi.org/10.1124/dmd.110.032060

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Research ArticleArticle

Pharmacokinetic Interaction between JBP485 and Cephalexin in Rats

Jian Zhang, Changyuan Wang, Qi Liu, Qiang Meng, Jian Cang, Huijun Sun, Ying Gao, Taiichi Kaku and Kexin Liu
Drug Metabolism and Disposition June 1, 2010, 38 (6) 930-938; DOI: https://doi.org/10.1124/dmd.110.032060
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