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Effects of CYP2C9 polymorphisms on the pharmacokinetics of R- and S-phenprocoumon in healthy volunteers

Kirchheiner, Juliaa; Ufer, Mikeb,c; Walter, Ev-Charlottea; Kammerer, Berndb; Kahlich, Rainerb; Meisel, Christiana; Schwab, Matthiasd; Gleiter, Christoph Hb; Rane, Andersc; Roots, Ivara; Brockmöller, Jürgene

Original Articles

CYP2C9 catalyses the biotransformation of the oral anticoagulants S-warfarin and R- and S-acenocoumarol. According to data obtained in vitro, phenprocoumon is also metabolized by CYP2C9 but the impact of the CYP2C9 polymorphism on phenprocoumon pharmacokinetics has not been studied. Twenty-six healthy heterozygous and homozygous carriers of the CYP2C9 alleles *1 (wild-type), *2 (Arg144Cys), and *3 (Ile359Leu) received a single oral dose of 12 mg of racemic phenprocoumon. Plasma and 12-h urine concentrations of both enantiomers and their monohydroxylated metabolites were measured by high-performance liquid chromatography with mass spectrometry detection. No significant effect of the CYP2C9 variants *2 and *3 on R-phenprocoumon pharmacokinetic parameters was detected, but S-phenprocoumon clearance tended to decrease with increasing number of CYP2C9*2 and *3 alleles. The ratios of S- to R-phenprocoumon plasma clearances were higher with a median of 0.95 in carriers of *1/*1 versus 0.65 in *3/*3 (P < 0.001 for trend). Plasma and urine concentrations of 4′-, 6- and 7-hydroxyphenprocoumon were significantly lower in homozygous carriers of the CYP2C9*2 and *3 variants compared to CYP2C9*1/*1. Carriers of CYP2C9*3/*3 had a median AUC of (R,S) 7-OH-phenprocoumon of only approximately 25% compared to the wild-type genotype. The AUC of (R,S) 6-OH-phenprocoumon was only approximately 50% in CYP2C9*3/*3 compared to the homozygous wild-type genotype. In conclusion, carriers of CYP2C9*2 and *3 alleles had a lower metabolic capacity regarding phenprocoumon hydroxylation than those with CYP2C9*1/*1. However, regarding phenprocoumon hydroxylation CYP2C9 genotypes had only marginal effects on S- and R-phenprocoumon total clearance in healthy volunteers.

aInstitute of Clinical Pharmacology, Charité, Humboldt University of Berlin, Germany, bInstitute of Pharmacology and Toxicology, Division of Clinical Pharmacology, University Tübingen, Germany, cDepartment of Laboratory Medicine, Division of Clinical Pharmacology, Karolinska Institutet, Stockholm, Sweden, dDr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany and eDepartment of Clinical Pharmacology, Georg August University of Göttingen, Germany.

Sponsorship: This study was supported by the German Ministry of Education and Research (GG 9845/5, 01 EC 0001, 031U209B), the Medical Faculty, University of Tübingen Grant no. AKF 72-0-0, and the Swedish Science Council (MFR 04496). M.U. is a recipient of research scholarship provided by the German Research Community (Uf 6/1-1).

Correspondence and requests for reprints to Dr Jürgen Brockmöller, Abteilung Klinische Pharmakologie, Georg-August-Universität Göttingen, Robert-Koch-Strasse 40, 37075 Göttingen, Germany. Tel: +49 551 39 5770; fax: +49 551 39 12767; e-mail:

Received 10 September 2003 Accepted 22 October 2003

© 2004 Lippincott Williams & Wilkins, Inc.