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ABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

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

College of Pharmacy, University of Michigan, Ann Arbor, Michigan (C.P.L., D.S., D.R.F., S.S.M., L.S.W., C.R., G.L.A.); Exploratory Biopharmaceutics and Stability, Drug Delivery Enablement, Pharmaceutical Research Institute, Bristol-Myers Squibb Company, New Brunswick, New Jersey (D.S.); Department of Pharmacy Practice, School of Pharmacy and Pharmacal Sciences, Purdue University, West Lafayette, Indiana (D.R.F.); Department of Internal Medicine, Division of Gastroenterology, University of Michigan Medical Center, Ann Arbor, Michigan (J.L.B.); Division of Gastroenterology, St. Joseph Mercy Hospital, Ann Arbor, Michigan (J.L.B.); and Department of Pharmacy, University Hospital, Ann Arbor, Michigan (L.S.W.)

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.

Address correspondence to: Gordon L. Amidon, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109-1065. E-mail: glamidon{at}umich.edu

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