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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Gene Expression in the Human Intestine and Correlation with Oral Valacyclovir Pharmacokinetic Parameters

Christopher P. Landowski, Duxin Sun, David R. Foster, Sujatha S. Menon, Jeffrey L. Barnett, Lynda S. Welage, Chandrasekharan Ramachandran and Gordon L. Amidon
Journal of Pharmacology and Experimental Therapeutics August 2003, 306 (2) 778-786; DOI: https://doi.org/10.1124/jpet.103.051011
Christopher P. Landowski
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Duxin Sun
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David R. Foster
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Sujatha S. Menon
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Jeffrey L. Barnett
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Lynda S. Welage
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Chandrasekharan Ramachandran
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Gordon L. Amidon
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Abstract

The transport of valacyclovir, the l-valyl ester of acyclovir, has been suggested to be mediated by several carrier-mediated pathways in cell culture and animal models. The role and importance of these transporters in modulating valacyclovir absorption in humans has not been determined, however. Recent advances in genomic technology have facilitated the rapid and simultaneous determination of global mRNA expression profiles for thousands of genes in tissue biopsies directly associated with the absorption process, thereby dramatically increasing the value of studies in humans. In this article, we describe correlations of pharmacokinetic parameters following oral valacyclovir or acyclovir administration with expression levels of intestinal genes in humans. Highly positive and significant correlations were observed with 4F2hc, an activator of cation-preferring amino acid transport systems, and human oligopeptide transporter (HPT1), an oligopeptide transporter expressed at higher levels in the human intestine compared with oligopeptide transporter (PEPT1). The validation of HPT1 microarray data with reverse transcription-polymerase chain reaction and the enhanced valacyclovir uptake in HeLa/HPT1 cells suggest that the role of HPT1 in transport of peptides and peptidomimetics drugs needs to be examined in more detail. The interrelation of 4F2hc and HPT1 in transport may be of interest. No significant correlations of valacyclovir pharmacokinetic parameters with PEPT1 and with organic cation or anion transporter expression levels were observed. The highly negative correlations observed with known efflux pumps such as MDR1 (P-glycoprotein) and MRP2 (cMOAT), as well as with the CYP450 IIIA subfamily may indicate that these proteins may regulate the cellular accumulation and metabolism of acyclovir.

Footnotes

  • This work was supported by National Institutes of Health Grant R01-GM37188 and by a CRC Grant 5M01-RR00042 through the National Institutes of Health.

  • DOI: 10.1124/jpet.103.051011.

  • ABBREVIATIONS: OAT, organic anion transporter; OCT, organic cation transporter; HPLC, high-performance liquid chromatography; RT-PCR, reverse transcription-polymerase chain reaction; PEPT1, oligopeptide transporter; HPT1, human oligopeptide transporter; MES, 4-morpholineethanesulfonic acid; AUC, area under the curve; CNT2, concentrative purine nucleoside transporter.

    • Received February 27, 2003.
    • Accepted May 1, 2003.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 306 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 306, Issue 2
1 Aug 2003
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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Gene Expression in the Human Intestine and Correlation with Oral Valacyclovir Pharmacokinetic Parameters

Christopher P. Landowski, Duxin Sun, David R. Foster, Sujatha S. Menon, Jeffrey L. Barnett, Lynda S. Welage, Chandrasekharan Ramachandran and Gordon L. Amidon
Journal of Pharmacology and Experimental Therapeutics August 1, 2003, 306 (2) 778-786; DOI: https://doi.org/10.1124/jpet.103.051011

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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Gene Expression in the Human Intestine and Correlation with Oral Valacyclovir Pharmacokinetic Parameters

Christopher P. Landowski, Duxin Sun, David R. Foster, Sujatha S. Menon, Jeffrey L. Barnett, Lynda S. Welage, Chandrasekharan Ramachandran and Gordon L. Amidon
Journal of Pharmacology and Experimental Therapeutics August 1, 2003, 306 (2) 778-786; DOI: https://doi.org/10.1124/jpet.103.051011
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