HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:
Sign In to gain access to subscriptions and/or personal tools.

This Article Full Text Full Text (PDF) All Versions of this Article: 0091270008327537v1 49/2/196    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Request Reprints Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Weiss, J. Articles by Mikus, G. Search for Related Content PubMed PubMed Citation Articles by Weiss, J. Articles by Mikus, G. Social Bookmarking                         What's this?

CYP2C19 Genotype Is a Major Factor Contributing to the Highly Variable Pharmacokinetics of Voriconazole

From the Department of Internal Medicine VI, Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Heidelberg, Germany (Dr Weiss, Dr ten Hoevel, Dr Burhenne, Dr Walter-Sack, Dr Rengelshausen, Dr Haefeli, Dr Mikus) and the Division of Clinical Chemistry, Department of Medicine, Albert-Ludwigs-University, Freiburg, Germany (Dr Hoffmann).

In vitro data on the metabolism of the antifungal voriconazole suggest that its pharmacokinetics might be influenced by the activity of CYP2C19, CYP2C9, and CYP3A. To elucidate the genetic influence of polymorphic enzymes on voriconazole metabolism, the authors pooled the pharmacokinetic data from 2 interaction studies in which 35 participants were enrolled according to their CYP2C19 genotype to receive a single 400-mg oral dose of voriconazole. Nine participants were homozygous for CYP2C19^*1/^*1, 8 heterozygous for ^*1/^*17, 11 heterozygous for ^*1/^*2, 2 heterozygous for ^*2/^*17, 4 homozygous for ^*2/^*2, and 1 with a double mutation CYP2C19^*2/^*2^*17. Nine (heterozygous) individuals were carriers of the CYP2C9^*2 or ^*3 variant alleles. Twenty-five participants did not express the CYP3A5 isozyme (^*3/^*3), whereas in 5 individuals, the ^*1/^*3 combination was present (active enzyme). In addition, the CYP2D6 genotype and 2 variants of the drug transporter MDR1 (C3435T and G2677T) were determined. Multiple regression analysis of voriconazole apparent oral clearance revealed that 49% of its variance can be explained solely by the CYP2C19 polymorphism (P < .0001). Including the other polymorphisms into the regression model did not show any significant contribution. The number of variant CYP2C19 alleles therefore explains a substantial part of the wide variability of voriconazole pharmacokinetics, whereas the presence of functional CYP3A5 and the CYP2C9 genotype had no significant impact on voriconazole exposure. Some minor contribution results from the MDR1 C3435T genotype.

Key Words: Voriconazole • CYP2C19 • CYP3A5 • MDR1 • pharmacokinetics

Address for reprints: Gerd Mikus, MD, Department of Internal Medicine VI, Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Im Neuenheimer Feld 410, D-69120 Heidelberg, Germany; e-mail: gerd.mikus{at}med.uni-heidelberg.de.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    Twitter    What's this?